Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them

ABSTRACT

Medicinal products containing the same which are useful in treating conditions requiring a pro-apoptotic agent.

The present invention relates to new bicyclic derivatives, to a processfor their preparation and to pharmaceutical compositions containingthem.

The compounds of the present invention are new and have very valuablepharmacological characteristics in the field of apoptosis andcancerology.

Apoptosis, or programmed cell death, is a physiological process that iscrucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such ascondensation of the nucleus, DNA fragmentation and also biochemicalphenomena such as the activation of caspases which cause damage to keystructural components of the cell, so inducing its disassembly anddeath. Regulation of the process of apoptosis is complex and involvesthe activation or repression of several intracellular signallingpathways (Cory S. et al., Nature Review Cancer 2002, 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increasedapoptosis is associated with neurodegenerative diseases such asParkinson's disease, Alzheimer's disease and ischaemia. Conversely,deficits in the implementation of apoptosis play a significant role inthe development of cancers and their chemoresistance, in auto-immunediseases, inflammatory diseases and viral infections. Accordingly,absence of apoptosis is one of the phenotypic signatures of cancer(Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated withnumerous pathologies. The involvement of proteins of the Bcl-2 family isdescribed in numerous types of cancer, such as colon cancer, breastcancer, small-cell lung cancer, non-small-cell lung cancer, bladdercancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia,lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc.Overexpression of the anti-apoptotic proteins of the Bcl-2 family isinvolved in tumorigenesis, in resistance to chemotherapy and in theclinical prognosis of patients affected by cancer. Notably, McI-1, ananti-apoptotic Bcl-2 family member, is overexpressed in various types ofcancer (Beroukhim R. et al., Nature 2010, 899-905). There is, therefore,a therapeutic need for compounds that inhibit the anti-apoptoticactivity of the proteins of the Bcl-2 family.

In addition to being new, the compounds of the present invention havepro-apoptotic properties making it possible to use them in pathologiesinvolving a defect in apoptosis, such as, for example, in the treatmentof cancer and of immune and auto-immune diseases.

The present invention relates more especially to compounds of formula(I):

wherein:

-   -   A represents the group

-   -   in which 1 is linked to the W group and 2 is linked to the        phenyl ring, wherein:        -   E represents a furyl, thienyl or pyrrolyl ring,        -   X₁, X₃, X₄ and X₅ independently of one another represent a            carbon atom or a nitrogen atom,        -   X₂ represents a C—R₂₁ group or a nitrogen atom, and

means that the ring is aromatic,

-   -   R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl        group, a linear or branched (C₂-C₆)alkenyl group, a linear or        branched (C₂-C₆)alkynyl group, a linear or branched        (C₁-C₆)polyhaloalkyl group, a hydroxy group, a        hydroxy(C₁-C₆)alkyl group, a linear or branched (C₁-C₆)alkoxy        group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,        -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,        —O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,        —NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,        —SO₂—NR₁₁R₁₁′, —SO₂-alkyl(C₁-C₆),    -   R₂, R₃, R₄ and R₅ independently of one another represent a        hydrogen atom, a halogen atom, a linear or branched (C₁-C₆)alkyl        group, a linear or branched (C₂-C₆)alkenyl group, a linear or        branched (C₂-C₆)alkynyl group, a linear or branched        (C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl        group, a linear or branched (C₁-C₆)alkoxy group, a        —S—(C₁-C₆)alkyl group, a cyano group, a nitro group,        -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,        —O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,        —NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,        —SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆),    -   or the substituents of the pair (R₁, R₂) form together with the        carbon atoms carrying them an aromatic or non-aromatic ring        composed of from 5 to 7 ring members, which may contain from 1        to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it        being understood that resulting ring may be substituted by from        1 to 2 groups selected from halogen, linear or branched        (C₁-C₆)alkyl, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′,        -alkyl(C₀-C₆)-Cy₁ or oxo,    -   R₆ and R₇ independently of one another represent a hydrogen        atom, a halogen atom, a linear or branched (C₁-C₆)alkyl group, a        linear or branched (C₂-C₆)alkenyl group, a linear or branched        (C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl,        a hydroxy group, a linear or branched (C₁-C₆)alkoxy group, a        —S—(C₁-C₆)alkyl group, a cyano group, a nitro group,        -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-Cy₁, -alkyl(C₀-C₆)-Cy₁,        -alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,        —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,        —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,        —SO₂-alkyl(C₁-C₆),    -   or the substituents of the pair (R₆, R₇), when grafted onto two        adjacent carbon atoms, form together with the carbon atoms        carrying them an aromatic or non-aromatic ring composed of from        5 to 7 ring members, which may contain from 1 to 3 heteroatoms        selected from oxygen, sulphur and nitrogen, it being understood        that resulting ring may be substituted by a group selected from        a linear or branched (C₁-C₆)alkyl group, —NR₁₃R₁₃′,        -alkyl(C₀-C₆)-Cy₁ or an oxo,    -   W represents a —CH₂— group, a —NH— group or an oxygen atom,    -   R₈ represents a hydrogen atom, a linear or branched (C₁-C₈)alkyl        group, a —CHR_(a)R_(b) group, an aryl group, a heteroaryl group,        an arylalkyl(C₁-C₆) group, or a heteroarylalkyl(C₁-C₆) group,    -   R₉ represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl        group, a linear or branched (C₂-C₆)alkenyl group, a linear or        branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,        -alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,        -alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a        halogen atom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′,    -   R₁₀ represents a hydrogen atom, a linear or branched        (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a        linear or branched (C₂-C₆)alkynyl group, an arylalkyl(C₁-C₆)        group, a cycloalkylalkyl(C₁-C₆) group, a linear or branched        (C₁-C₆)polyhaloalkyl, -alkyl(C₁-C₆)—O—Cy₄, or the substituents        of the pair (R₉, R₁₀), when grafted onto two adjacent carbon        atoms, form together with the carbon atoms carrying them an        aromatic or non-aromatic ring composed of from 5 to 7 ring        members, which may contain from 1 to 3 heteroatoms selected from        oxygen, sulphur and nitrogen,    -   R₁₁ and R₁₁′ independently of one another represent a hydrogen        atom, a linear or branched (C₁-C₆)alkyl group, or the        substituents of the pair (R₁₁, R₁₁′) form together with the        nitrogen atom carrying them an aromatic or non-aromatic ring        composed of from 5 to 7 ring members, which may contain in        addition to the nitrogen atom from 1 to 3 heteroatoms selected        from oxygen, sulphur and nitrogen, it being understood that the        nitrogen in question may be substituted by a group representing        a hydrogen atom, or a linear or branched (C₁-C₆)alkyl group,    -   R₁₂ represents -Cy₅, -Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆,        -Cy₅-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆,        -Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇, —C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁,        —NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁₁, —SO₂—R₁₁, —C(O)—OR₁₁, or        —NH—C(O)—NH—R₁₁,    -   R₁₃, R₁₃′, R₁₅ and R₁₅′ independently of one another represent a        hydrogen atom, or an optionally substituted linear or branched        (C₁-C₆)alkyl group,    -   R₁₄ represents a hydrogen atom, a hydroxy group or a        hydroxy(C₁-C₆)alkyl group,    -   R₂₁ represents a hydrogen atom, a halogen atom, a linear or        branched (C₁-C₆)alkyl group, or a cyano group,    -   R_(a) represents a hydrogen atom or a linear or branched        (C₁-C₆)alkyl group,    -   R_(b) represents a —O—C(O)—O—R_(c) group, a —O—C(O)—NR_(c)R_(c)′        group, or a —O—P(O)(OR_(c))₂ group,    -   R_(c) and R_(c)′ independently of one another represent a        hydrogen atom, a linear or branched (C₁-C₈)alkyl group, a        cycloalkyl group, a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a        (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl group, or the substituents of        the pair (R_(c), R_(c)′) form together with the nitrogen atom        carrying them a non-aromatic ring composed of from 5 to 7 ring        members, which may contain in addition to the nitrogen atom from        1 to 3 heteroatoms selected from oxygen and nitrogen, it being        understood that the nitrogen in question may be substituted by a        group representing a linear or branched (C₁-C₆)alkyl group,    -   Cy₁, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇ independently of one        another, represent a cycloalkyl group, a heterocycloalkyl group,        an aryl group, or a heteroaryl group,    -   n is an integer equal to 0 or 1,        it being understood that:    -   “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenyl        group,    -   “heteroaryl” means any mono- or bi-cyclic group composed of from        5 to 10 ring members, having at least one aromatic moiety and        containing from 1 to 3 heteroatoms selected from oxygen, sulphur        and nitrogen,    -   “cycloalkyl” means any mono- or bi-cyclic non-aromatic        carbocyclic group containing from 3 to 10 ring members,    -   “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic        carbocyclic group containing from 3 to 10 ring members, and        containing from 1 to 3 heteroatoms selected from oxygen, sulphur        and nitrogen, which may include fused, bridged or spiro ring        systems, it being possible for the aryl, heteroaryl, cycloalkyl        and heterocycloalkyl groups so defined and the alkyl, alkenyl,        alkynyl, alkoxy groups, to be substituted by from 1 to 4 groups        selected from optionally substituted linear or branched        (C₁-C₆)alkyl, optionally substituted linear or branched        (C₂-C₆)alkenyl, optionally substituted linear or branched        (C₂-C₆)alkynyl, optionally substituted linear or branched        (C₁-C₆)alkoxy, optionally substituted (C₁-C₆)alkyl-S—, hydroxy,        oxo (or N-oxide where appropriate), nitro, cyano, —C(O)—OR′,        —O—C(O)—R′, —C(O)—NR′R″, —O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″,        —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂, linear or branched        (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, or an        aldohexose of formula:

in which each R′ is independent;it being understood that R′ and R″ independently of one anotherrepresent a hydrogen atom or an optionally substituted linear orbranched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation,with the proviso that

cannot represent

their enantiomers, diastereoisomers and atropisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.

Advantageously, the present invention relates to compounds of formula(I) wherein:

-   -   R₁ and R₂ independently of one another represent a halogen atom,        a linear or branched (C₁-C₆)alkyl group, a hydroxy group, a        linear or branched (C₁-C₆)alkoxy group,    -   or the substituents of the pair (R₁, R₂) form together with the        carbon atoms carrying them an aromatic ring composed of from 5        to 7 ring members, which may contain from 1 to 3 nitrogen atoms,    -   R₃ represents a hydrogen atom, a halogen atom, a linear or        branched (C₁-C₆)alkyl group, a hydroxy group, a linear or        branched (C₁-C₆)alkoxy group, or —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,    -   R₄ and R₅ independently of one another represent a hydrogen        atom, a halogen atom, a linear or branched (C₁-C₆)alkyl group, a        hydroxy group, a linear or branched (C₁-C₆)alkoxy group,    -   R₆ and R₇ independently of one another represent a hydrogen        atom, a halogen atom, a linear or branched (C₁-C₆)alkyl group, a        linear or branched (C₁-C₆)polyhaloalkyl group, a hydroxy group,        a linear or branched (C₁-C₆)alkoxy group, a cyano group, a nitro        group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, -alkyl(C₀-C₆)-Cy₁,        —O-alkyl(C₁-C₆)—R₁₂, or —C(O)—NR₁₁R₁₁′,    -   R₈ represents a hydrogen atom, a linear or branched (C₁-C₈)alkyl        group, or a —CHR_(a)R_(b) group,    -   R₉ represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl        group, a linear or branched (C₂-C₆)alkenyl group, a linear or        branched (C₂-C₆)alkynyl group, -Cy₂, or a halogen atom,    -   R₁₀ represents a hydrogen atom, a linear or branched        (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a        linear or branched (C₂-C₆)alkynyl group, an arylalkyl(C₁-C₆)        group, a cycloalkylalkyl(C₁-C₆) group, a linear or branched        (C₁-C₆)polyhaloalkyl, or -alkyl(C₁-C₆)—O—Cy₄,    -   or the substituents of the pair (R₉, R₁₀) when grafted onto two        adjacent carbon atoms, form together with the carbon atoms        carrying them a non-aromatic ring composed of from 5 to 7 ring        members, which may contain from 1 to 3 heteroatoms selected from        oxygen, sulphur and nitrogen,    -   R₁₁ and R₁₁′ independently of one another represent a hydrogen        atom, a linear or branched (C₁-C₆)alkyl group, or the        substituents of the pair (R₁₁, R₁₁′) form together with the        nitrogen atom carrying them a non-aromatic ring composed of from        5 to 7 ring members, which may contain in addition to the        nitrogen atom from 1 to 3 heteroatoms selected from oxygen and        nitrogen, it being understood that the nitrogen in question may        be substituted by a group representing a linear or branched        (C₁-C₆)alkyl group,    -   R₁₂ represents -Cy₅ or -Cy₅-alkyl(C₀-C₆)-Cy₆,    -   W represents a —NH— group or an oxygen atom,        it being possible for the aryl, heteroaryl, cycloalkyl and        heterocycloalkyl groups so defined and the alkyl, alkenyl,        alkynyl, alkoxy groups, to be substituted by from 1 to 4 groups        selected from optionally substituted linear or branched        (C₁-C₆)alkyl, optionally substituted linear or branched        (C₁-C₆)alkoxy, hydroxy, oxo (or N-oxide where appropriate),        —C(O)—OR′, —C(O)—NR′R″, —O—C(O)—NR′R″, —NR′R″, —O—P(O)(OR′)₂,        —O—P(O)(O⁻M⁺)₂, linear or branched (C₁-C₆)polyhaloalkyl,        halogen, or an aldohexose of formula:

in which each R′ is independent;it being understood that R′ and R″ independently of one anotherrepresent a hydrogen atom or an optionally substituted linear orbranched (C₁-C₆)alkyl group and M⁺ represents a pharmaceuticallyacceptable monovalent cation.

More especially, compounds of formula (I) to which preference is givenare compounds wherein n is an integer equal to 1.

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-a):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₄, X₁, X₂, X₃ and W are asdefined for formula (I). More especially, compounds of formula (I-a) towhich preference is given are compounds wherein

More particularly, compounds of formula (I-a) to which preference isgiven are compounds wherein

Advantageously,

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-b):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₄, X₁, X₂, X₃ and W are asdefined for formula (I). More especially, compounds of formula (I-b) towhich preference is given are compounds wherein

Advantageously,

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-c):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₄, X₁, X₂, X₃ and Ware as defined for formula (I). More especially, compounds of formula(I-c) to which preference is given are compounds wherein

More particularly, compounds of formula (I-c) to which preference isgiven are compounds wherein

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-d):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₄, X₁, X₂, X₃ and Ware as defined for formula (I). More especially, compounds of formula(I-d) to which preference is given are compounds wherein

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-e):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₄, X₁, X₂, X₃ and W are asdefined for formula (I). More especially, compounds of formula (I-e) towhich preference is given are compounds wherein

Advantageously,

Compounds of formulae (I-a), (I-b), (I-c) and (I-e) are particularlypreferred. Compounds of formulae (I-a) and (I-b) are even morepreferred.

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-f):

wherein E, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₄, X₁, X₂, X₃, X₄,X₅ and W are as defined for formula (I).

Atropisomers are stereoisomers arising because of hindered rotationabout a single bond, where energy differences due to steric strain orother contributors create a barrier to rotation that is high enough toallow for isolation of individual conformers. For example, for compoundsof formula (I-b) (the same can be done for compounds of formula (I-a),(I-c), (I-d) and (I-e)), atropisomers are as follows:

Preferred atropisomer is (S_(a)) for compounds of formula (I-a), (I-b),(I-c) and (I-d). Preferred atropisomer is (R_(a)) for compounds offormula (I-e).

Advantageously, at least one of the groups selected from R₂, R₃, R₄ andR₅ does not represent a hydrogen atom.

Preferably, R₁₄ represents a hydrogen atom.

R₂₁ represents preferably a hydrogen atom, a fluorine atom, a methylgroup or a cyano group. More preferably, R₂₁ represents a hydrogen atomor a fluorine atom. Even more preferably, R₂₁ represents a hydrogenatom.

In the preferred compounds of the invention, R₁ represents a linear orbranched (C₁-C₆)alkyl group or a halogen atom. More preferably, R₁represents a methyl group, an ethyl group, a bromine atom or a chlorineatom. Even more preferably, R₁ represents a methyl group or an ethylgroup.

Advantageously, R₂ represents a halogen atom, a hydroxy group, a linearor branched (C₁-C₆)alkoxy group. More preferably, R₂ represents amethoxy group, a hydroxy group, a fluorine atom, a bromine atom or achlorine atom. Even more preferably, R₂ represents a chlorine atom.

In some preferred embodiment of the invention, when the substituents ofthe pair (R₁, R₂) form together with the carbon atoms carrying them anaromatic ring,

R₃ advantageously represents a hydrogen atom, a hydroxy group, a linearor branched (C₁-C₆)alkoxy group or —O-alkyl(C₁-C₆)—NR₁₁R₁₁′.Advantageously, R₃ represents —O-alkyl(C₁-C₆)—NR₁₁R₁₁′.

R₄ and R₅ preferably represent a hydrogen atom.

In an advantageous embodiment, the substituents of the pair (R₁, R₅) areidentical and the substituents of the pair (R₂, R₄) are identical. Inthe preferred compounds of the invention, the substituents of the pair(R₁, R₅) are identical and represent a (C₁-C₆)alkyl group, preferably amethyl group, whereas the substituents of the pair (R₂, R₄) areidentical and represent a halogen atom, preferably a chlorine atom, or ahydrogen atom.

In the preferred compounds of the invention,

wherein R₁₁ and R₁₁′ are as defined for formula (I).

In another embodiment of the invention, R₆ represents a hydrogen atom,an optionally substituted linear or branched (C₁-C₆)alkoxy group or a—O-alkyl(C₁-C₆)—R₁₂ group.

Advantageously, R₆ represents a 2,2,2-trifluoroethoxy group, a methoxygroup, or a —O-alkyl(C₁-C₆)—R₁₂ group.

R₇ preferably represents a hydrogen atom.

In the preferred compounds of the invention,

wherein R₁₂ is as defined for formula (I).

In another embodiment of the invention, an advantageous possibilityconsists of compounds of formula (I-g):

wherein R₁, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₁′, R₁₄, X₁, X₂, X₃, X₄, X₅, Wand E are as defined for formula (I).

Preferably, R₈ represents a hydrogen atom, a —CHR_(a)R_(b) group, anoptionally substituted linear or branched (C₁-C₈)alkyl group, or aheteroarylalkyl(C₁-C₆) group. Preferably, R₈ represents a —CHR_(a)R_(b)group in which R_(a) represents a hydrogen atom or a methyl group andR_(b) represents a —O—C(O)—O—(C₁-C₈)alkyl group; a —O—C(O)—O-cycloalkylgroup; a —O—C(O)—NR_(c)R_(c)′ group, in which R_(c) and R_(c)′independently of one another represent a hydrogen atom, a linear orbranched (C₁-C₈)alkyl group, a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl group, or the substituents of the pair(R_(c), R_(c)′) form together with the nitrogen atom carrying them anon-aromatic ring composed of from 5 to 7 ring members, which maycontain in addition to the nitrogen atom from 1 to 3 heteroatomsselected from oxygen and nitrogen; or a —O—P(O)(OH)₂ group. Preferred R₈groups are as follows: hydrogen; methyl; ethyl;(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; a —CHR_(a)R_(b) group in whichR_(a) represents a methyl group and R_(b) represents a —O—C(O)—O—CH₂CH₃group or a —O—C(O)—N(CH₃)₂ group. Even more preferably, R₈ representshydrogen.

In the preferred compounds of the invention, R₉ represents a hydrogenatom, a halogen atom, a linear or branched (C₁-C₆)alkyl group, a linearor branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynylgroup, an aryl group or a heteroaryl group. More preferably, R₉represents a prop-1-yn-1-yl group, a phenyl group or a furan-2-yl group.In a more preferred embodiment, R₉ represents a prop-1-yn-1-yl group, a4-fluorophenyl group or a 5-fluorofuran-2-yl group. Even morepreferentially, R₉ represents a 4-fluorophenyl group.

In the advantageous possibility consisting in compounds of formula(I-c), preferred R₁₀ groups are as follows: hydrogen; methyl; isopropyl;2,2,2-trifluoroethyl; benzyl; 4-methoxybenzyl; phenethyl;3-phenyl-propyl; cyclopropylmethyl; cyclopentylethyl;naphthalen-1-ylmethyl; 2-(naphthalen-1-yloxy)ethyl; but-2-yn-1-yl;prop-2-en-1 yl; but-3-en-1-yl. In another embodiment, the substituentsof the pair (R₉, R₁₀) when grafted onto two adjacent atoms, formtogether with the carbon and nitrogen atoms carrying them a non-aromaticring composed of from 5 to 6 ring members.

In the advantageous possibility consisting in compounds of formula(I-d), R₁₀ preferably represents a hydrogen atom or a halogen atom.

In the preferred compounds of the invention, R₁₁ and R₁₁′ independentlyof one another represent a linear or branched (C₁-C₆)alkyl group, or thesubstituents of the pair (R₁₁, R₁₁′) form together with the nitrogenatom carrying them a non-aromatic ring composed of from 5 to 7 ringmembers, which may contain in addition to the nitrogen atom from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, it beingunderstood that the nitrogen in question may be substituted by a grouprepresenting a hydrogen atom, a linear or branched (C₁-C₆)alkyl group.More preferably, R₁₁ and R₁₁′ represent a methyl group, or thesubstituents of the pair (R₁₁, R₁₁′) form together a4-methyl-piperazinyl group or a 4-ethyl-piperazinyl group. In a morepreferred embodiment, the substituents of the pair (R₁₁, R₁₁′) formtogether a 4-methyl-piperazinyl group. In another preferred embodiment,R₁₁ and R₁₁′ represent a methyl group.

Advantageously, R₁₂ represents -Cy₅ or -Cy₅-alkyl(C₀-C₆)-Cy₆.Preferably, R₁₂ represents -Cy₅ or -Cy₅-Cy₆.

Cy₅ preferably represents a heteroaryl group, particularly, apyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinylgroup or a pyridinyl group. More preferably, Cy₅ represents apyrimidin-4-yl group, a pyrazol-5-yl group, or a pyrazin-2-yl group. Inthe preferred compounds of the invention, Cy₅ represents apyrimidin-4-yl group.

In another embodiment of the invention, Cy₅ represents a heteroarylgroup which is substituted by an optionally substituted linear orbranched (C₁-C₆)alkyl group, an optionally substituted linear orbranched (C₁-C₆)alkoxy group, a —NR′R″ group, or a linear or branched(C₁-C₆)polyhaloalkyl group, it being understood that R′ and R″independently of one another represent a hydrogen atom or an optionallysubstituted linear or branched (C₁-C₆)alkyl group.

Cy₆ preferably represents a phenyl group.

Other compounds of the invention to which preference is given are thosewherein,

-   -   R₁₂ represents,

in which p is an integer equal to 0 or 1 and R₁₆ represents a hydrogenatom, a hydroxy group, an optionally substituted linear or branched(C₁-C₆)alkyl group, a linear or branched (C₁-C₆)alkoxy group, a—O—(CHR₁₇—CHR₁₈—O)_(q)—R′ group, a —O—P(O)(OR′)₂ group, a —O—P(O)(O⁻M⁺)₂group, a —O—C(O)—NR₁₉R₂₀ group, a di(C₁-C₆)alkylamino(C₁-C₆)alkoxygroup, a halogen atom, or an aldohexose of formula:

in which each R′ is independent;it being understood that:

-   -   R′ represents a hydrogen atom or a linear or branched        (C₁-C₆)alkyl group,    -   R₁₇ represents a hydrogen atom or a (C₁-C₆)alkoxy(C₁-C₆)alkyl        group,    -   R₁₈ represents a hydrogen atom or a hydroxy(C₁-C₆)alkyl group,    -   R₁₉ represents a hydrogen atom or a (C₁-C₆)alkoxy(C₁-C₆)alkyl        group,    -   R₂₀ represents a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a        —(CH₂)_(r)—NR₁₁R₁₁′ group or a        —(CH₂)_(r)—O—(CHR₁₇—CHR₁₈—O)_(q)—R′ group,    -   q is an integer equal to 1, 2 or 3 and r is an integer equal to        0 or 1,    -   M⁺ represents a pharmaceutically acceptable monovalent cation.

The aldohexose according to the invention is preferably D-mannose.Preferably, the group —(CH₂)_(p)—R₁₆ is located at ortho position of thephenyl group.

Among the preferred compounds of the invention there may be mentioned:

-   (2R)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid;-   (2R)-2-{[5-{3-chloro-2-ethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid;-   N-[(5S_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine;-   (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzothiophen-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic    acid;-   (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic    acid;-   (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-fluoro-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid;-   (2R)-2-{[3-{(3S_(a))-3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-methyl-1H-indol-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid;-   (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid;-   (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxy    phenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid;-   1-[(dimethylcarbamoyl)oxy]ethyl    (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;-   1-[(ethoxycarbonyl)oxy]ethyl    (2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;-   N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine;-   N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanine;-   2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)    pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

The invention relates also to a process for the preparation of compoundsof formula (I), which process is characterized in that there is used asstarting material the compound of formula (II-a):

wherein Z₁ represents bromine or iodine, Z₂ represents chlorine, bromineor hydroxy, and A is as defined for formula (I) in which 1 is linked tothe Z₂ group and 2 is linked to the Z₁ group,which compound of formula (II-a) is subjected to coupling with acompound of formula (III):

wherein R₆, R₇, R₁₄, W and n are as defined for formula (I), and Alkrepresents a linear or branched (C₁-C₆)alkyl group, to yield thecompound of formula (IV):

wherein R₆, R₇, R₁₄, A, W and n are as defined for formula (I), and Z₁and Alk are as defined before,compound of formula (IV) which is further subjected to coupling withcompound of formula (V):

wherein R₁, R₂, R₃, R₄ and R₅ are as defined for formula (I), and R_(B1)and R_(B2) represent a hydrogen atom, a linear or branched (C₁-C₆) alkylgroup, or R_(B1) and R_(B2) form with the oxygen carrying them anoptionally methylated ring,to yield the compound of formula (VI):

wherein R₁, R₂, R₃ R₄, R₅, R₆, R₇, R₁₄, A, W and n are as defined forformula (I) and Alk is as defined before,the Alk-O—C(O)— ester function of which compound of formula (VI) ishydrolyzed to yield the carboxylic acid, which may optionally be reactedwith an alcohol of formula R₈′—OH or a chlorinated compound of formulaR₈′—Cl wherein R₈′ represents a linear or branched (C₁-C₈)alkyl group, a—CHR_(a)R_(b) group, an aryl group, a heteroaryl group, anarylalkyl(C₁-C₆) group, or a heteroarylalkyl(C₁-C₆) group, R_(a) andR_(b) are as defined for formula (I),to yield the compound of formula (I), which may be purified according toa conventional separation technique, which is converted, if desired,into its addition salts with a pharmaceutically acceptable acid or baseand which is optionally separated into its isomers according to aconventional separation technique, it being understood that at anymoment considered appropriate during the course of the process describedabove, some groups (hydroxy, amino . . . ) of the starting reagents orof the synthesis intermediates can be protected, subsequentlydeprotected and functionalized, as required by the synthesis.

In another embodiment of the invention, compounds of formula (I) may beobtained using an alternative process, which process is characterised inthat there is used as starting material the compound of formula (II-b):

wherein Z₃ represents iodine, Z₄ represents chlorine, hydroxy, and A isas defined for formula (I) in which 1 is linked to the Z₄ group and 2 islinked to the Z₃ group,which compound of formula (II-b) is subjected to coupling with acompound of formula (V):

wherein R₁, R₂, R₃, R₄ and R₅ are as defined for formula (I), and R_(B1)and R_(B2) represent a hydrogen atom, a linear or branched (C₁-C₆) alkylgroup, or R_(B1) and R_(B2) form with the oxygen carrying them anoptionally methylated ring,to yield the compound of formula (VII):

wherein R₁, R₂, R₃ R₄, R₅ and A are as defined for formula (I), and Z₄is as defined before,compound of formula (VII) which is further subjected to coupling withcompound of formula (III):

wherein R₆, R₇, R₁₄, W and n are as defined for formula (I), and Alkrepresents a linear or branched (C₁-C₆)alkyl group,to yield the compound of formula (VI):

wherein R₁, R₂, R₃ R₄, R₅, R₆, R₇, R₁₄, A, W and n are as defined forformula (I) and Alk is as defined before,the Alk-O—C(O)— ester function of which compound of formula (VI) ishydrolyzed to yield the carboxylic acid, which may optionally be reactedwith an alcohol of formula R₈′—OH or a chlorinated compound of formulaR₈′—Cl wherein R₈′ represents a linear or branched (C₁-C₈)alkyl group, a—CHR_(a)R_(b) group, an aryl group, a heteroaryl group, anarylalkyl(C₁-C₆) group, or a heteroarylalkyl(C₁-C₆) group, R_(a) andR_(b) are as defined for formula (I),to yield the compound of formula (I), which may be purified according toa conventional separation technique, which is converted, if desired,into its addition salts with a pharmaceutically acceptable acid or baseand which is optionally separated into its isomers according to aconventional separation technique, it being understood that at anymoment considered appropriate during the course of the process describedabove, some groups (hydroxy, amino . . . ) of the starting reagents orof the synthesis intermediates can be protected, subsequentlydeprotected and functionalized, as required by the synthesis.

The compounds of formulae (II-a), (II-b), (III), (V), R₈′—OH and R₈′-CLare either commercially available or can be obtained by the personskilled in the art using conventional chemical reactions described inthe literature.

Pharmacological study of the compounds of the invention has shown thatthey have pro-apoptotic properties. The ability to reactivate theapoptotic process in cancerous cells is of major therapeutic interest inthe treatment of cancers and of immune and auto-immune diseases.

More especially, the compounds according to the invention will be usefulin the treatment of chemo- or radio-resistant cancers.

Among the cancer treatments envisaged there may be mentioned, withoutimplying any limitation, treatment of cancers of the bladder, brain,breast and uterus, chronic lymphoid leukemia, cancer of the colon,esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia,lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer,non-small-cell lung cancer, prostate cancer, pancreatic cancer andsmall-cell lung cancer.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) in combination with oneor more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration, especially tablets or dragées, sublingualtablets, sachets, paquets, capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels, and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the administration route, the nature of the therapeutic indication, orof any associated treatments, and ranges from 0.01 mg to 1 g per 24hours in one or more administrations.

Furthermore, the present invention relates also to the combination of acompound of formula (I) with an anticancer agent selected from genotoxicagents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinaseinhibitors and antibodies, and also to pharmaceutical compositionscomprising that type of combination and their use in the manufacture ofmedicaments for use in the treatment of cancer.

Advantageously, the present invention relates to the combination of acompound of formula (I) with an EGFR inhibitor, and also topharmaceutical compositions comprising that type of combination.

In another embodiment, the present invention relates to the combinationof a compound of formula (I) with a mTOR/PI3K inhibitor, and also topharmaceutical compositions comprising that type of combination.

In a preferred embodiment, the present invention relates to thecombination of a compound of formula (I) with a MEK inhibitor, and alsoto pharmaceutical compositions comprising that type of combination.

Preferably, the present invention relates to the combination of acompound of formula (I) with a HER2 inhibitor, and also topharmaceutical compositions comprising that type of combination.

Advantageously, the present invention relates to the combination of acompound of formula (I) with a RAF inhibitor, and also to pharmaceuticalcompositions comprising that type of combination.

In another embodiment, the present invention relates to the combinationof a compound of formula (I) with a EGFR/HER2 inhibitor, and also topharmaceutical compositions comprising that type of combination.

In a preferred embodiment, the present invention relates to thecombination of a compound of formula (I) with a taxane, and also topharmaceutical compositions comprising that type of combination.

In another embodiment, the present invention relates to the combinationof a compound of formula (I) with a proteasome inhibitor, animmunomodulator or an alkylating agent, and also to pharmaceuticalcompositions comprising that type of combination.

The combination of a compound of formula (I) with an anticancer agentmay be administered simultaneously or sequentially. The administrationroute is preferably the oral route, and the corresponding pharmaceuticalcompositions may allow the instantaneous or delayed release of theactive ingredients. The compounds of the combination may moreover beadministered in the form of two separate pharmaceutical compositions,each containing one of the active ingredients, or in the form of asingle pharmaceutical composition, in which the active ingredients arein admixture.

The compounds of the invention may also be used in combination withradiotherapy in the treatment of cancer.

Finally, the compounds of the invention may be linked to monoclonalantibodies or fragments thereof or linked to scaffold proteins that canbe related or not to monoclonal antibodies.

Antibody fragments must be understood as fragments of Fv, scFv, Fab,F(ab′)2, F(ab′), scFv-Fc type or diabodies, which generally have thesame specificity of binding as the antibody from which they aredescended. According to the present invention, antibody fragments of theinvention can be obtained starting from antibodies by methods such asdigestion by enzymes, such as pepsin or papain, and/or by cleavage ofthe disulfide bridges by chemical reduction. In another manner, theantibody fragments comprised in the present invention can be obtained bytechniques of genetic recombination likewise well known to the personskilled in the art or else by peptide synthesis by means of, forexample, automatic peptide synthesizers such as those supplied by thecompany Applied Biosystems, etc.

Scaffold proteins that can be related or not to monoclonal antibodiesare understood to mean a protein that contains or not an immunoglobulinfold and that yields a binding capacity similar to a monoclonalantibody. The man skilled in the art knows how to select the proteinscaffold. More particularly, it is known that, to be selected, such ascaffold should display several features as follow (Skerra A., J. Mol.Recogn. 2000, 13, 167-187): phylogenetically good conservation, robustarchitecture with a well-known three-dimensional molecular organization(such as, for example, crystallography or NMR), small size, no or only alow degree of post-translational modifications, easy to produce, expressand purify. Such a protein scaffold can be, but without limitation, astructure selected from the group consisting in fibronectin andpreferentially the tenth fibronectin type III domain (FNfn10),lipocalin, anticalin (Skerra A., J. Biotechnol. 2001, 74(4):257-75), theprotein Z derivative from the domain B of staphylococcal protein A,thioredoxin A or any protein with a repeated domain such as an “ankyrinrepeat” (Kohl et al., PNAS 2003, 100(4), 1700-1705), “armadillo repeat”,“leucine-rich repeat” or “tetratricopeptide repeat”. There could also bementioned a scaffold derivative from toxins (such as, for example,scorpion, insect, plant or mollusc toxins) or protein inhibitors ofneuronal nitric oxide synthase (PIN).

The following Preparations and Examples illustrate the invention but donot limit it in any way.

GENERAL PROCEDURES

All reagents obtained from commercial sources were used without furtherpurification.

Anhydrous solvents were obtained from commercial sources and usedwithout further drying.

Flash chromatography was performed on ISCO CombiFlash Rf 200i withpre-packed silica-gel cartridges (RediSep® R_(f) Gold High Performance).

Thin layer chromatography was conducted with 5×10 cm plates coated withMerck Type 60 F254 silica-gel.

Microwave heating was performed in an Anton Parr MonoWave or CEMDiscover® instrument.

Preparative HPLC purifications were performed on an Armen Spot LiquidChromatography system with a Gemini-NX® 10 μM C18, 250 mm×50 mm i.d.column running at a flow rate of 118 mL min⁻¹ with UV diode arraydetection (210-400 nm) using 25 mM aqueous NH₄HCO₃ solution and MeCN aseluents unless specified otherwise.

Analytical LC-MS: The compounds of the present invention werecharacterized by high performance liquid chromatography-massspectroscopy (HPLC-MS) on Agilent HP1200 with Agilent 6140 quadrupoleLC/MS, operating in positive or negative ion electrospray ionisationmode. Molecular weight scan range is 100 to 1350. Parallel UV detectionwas done at 210 nm and 254 nm. Samples were supplied as a 1 mM solutionin ACN, or in THF/H₂O (1:1) with 5 μL loop injection. LCMS analyses wereperformed on two instruments, one of which was operated with basic, andthe other with acidic eluents.

Basic LCMS: Gemini-NX, 3 am, C18, 50 mm×3.00 mm i.d. column at 23° C.,at a flow rate of 1 mL min⁻¹ using 5 mM ammonium bicarbonate (Solvent A)and acetonitrile (Solvent B) with a gradient starting from 100% SolventA and finishing at 100% Solvent B over various/certain duration of time.

Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 am, 50 mm×4.6 mm i.d. column at40° C., at a flow rate of 1 mL min⁻¹ using 0.02% v/v aqueous formic acid(Solvent A) and 0.02% v/v formic acid in acetonitrile (Solvent B) with agradient starting from 100% Solvent A and finishing at 100% Solvent Bover various/certain duration of time.

¹H-NMR measurements were performed on Bruker Avance III 500 MHzspectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-d₆or CDCl₃ as solvent. 1H NMR data is in the form of delta values, givenin part per million (ppm), using the residual peak of the solvent (2.50ppm for DMSO-d₆ and 7.26 ppm for CDCl₃) as internal standard. Splittingpatterns are designated as: s (singlet), d (doublet), t (triplet), q(quartet), quint (quintet), m (multiplet), br s (broad singlet), dd(doublet of doublets), td (triplet of doublets), dt (doublet oftriplets), ddd (doublet of doublet of doublets).

Combination gas chromatography and low resolution mass spectrometry wereperformed on Agilent 6850 gas chromatograph and Agilent 5975C massspectrometer using 15 m×0.25 mm column with 0.25 m HP-5MS coating andhelium as carrier gas. Ion source: EI+, 70 eV, 230° C., quadrupole: 150°C., interface: 300° C.

HRMS were determined on a Shimadzu IT-TOF, ion source temperature 200°C., ESI+/−, ionization voltage: (+−)4.5 kV. Mass resolution min. 10000.

Elementary analyses were performed on a Thermo Flash EA 1112 ElementalAnalyzer.

List of Abbreviations

Abbreviation Name 2-Me-THF 2-methyl-tetrahydrofurane abs. absolute Acacetyl AIBN 2-[(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrileAtaPhos bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) cc. concentrated dbadibenzylideneacetone DCM methylene chloride DEAD diethylazodicarboxylate DEE diethyl ether DIPA diisopropylamine DIPEAdiisopropylethylamine DMA dimethylacetamide DME 1,2-dimethoxyethane DMFdimethylformamide DMSO dimethyl sulfoxide dppf1,1′-bis(diphenylphosphino)ferrocene DTAD di-tert-butyl azodicarboxylateEDC · HCl N-(3-dimethylaminopropy1)-N′-ethylcarbodiimide hydrochlorideeq. equivalent Et ethyl HILIC hydrophilic interaction liquidchromatography HMDS hexamethyldisilazane ^(i)Pr isopropyl LDA lithiumdiisopropylamide MCPBA meta-chloroperoxybenzoic acid Me methyl MeCNacetonitrile MTBE methyl tert-butyl ether MW microwave NBSN-bromosuccinimide ^(n)Bu n-butyl NCS N-chlorosuccinimide Ph phenyl PPApolyphospholic acid rac. racemic r.t. room temperature S₂Me₂ dimethyldisulfide SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TBAFtetrabutyl ammonium fluoride TBAOH tetrabutyl ammonium hydroxyde ^(t)Butert-butyl TEA triethylamine TFA trifluoroacetic acid THFtetrahydrofurane TIPSCl triisopropylsilyl chloride TLC thin layerchromatography Ts tosyl X-Phos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Procedure Ia

1 eq. Preparation 1a, 2 eq. from the appropriate lactic esterderivative, 10 mL/mmol ^(t)BuOH and 5 eq. Cs₂CO₃ were placed in a flaskand stirred at 55° C. until no further conversion was observed. Then themixture was concentrated under reduced pressure, neutralized with IMaqueous HCl solution, diluted with brine and extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via flash chromatography using heptane and EtOAc as eluentsunless otherwise stated.

General Procedure Ib

1 eq. Preparation 1a, 2 eq. from the appropriate amino acid derivative,10 mL/mmol DMSO and 3 eq. K₂CO₃ were placed in a flask and stirred at45° C. until no further conversion was observed. Then the mixture wasneutralized with 1 M aqueous HCl solution, diluted with brine andextracted with DCM. The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude product was purified via HILIC chromatography unless otherwisestated.

General Procedure II Step A

1 eq. from the appropriate 5-bromo-furo[2,3-d]pyrimidyl-lactic esterderivative, 1.25 eq. from the appropriate boronic acid derivative, 10mol % AtaPhos and 3 eq. Cs₂CO₃ were dissolved in a 1:1 mixture ofdioxane and water (10 mL/mmol 5-bromo-furo[2,3-d]pyrimidyl-lactic esterderivative) and stirred at 105° C. in a MW reactor until no furtherconversion was observed. Then the mixture was neutralized with IMaqueous HCl solution, diluted with brine and extracted with THF. Thecombined organic phases were dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The crude product was purifiedusing preparative reversed phase chromatography using 25 mM aqueousNH₄HCO₃ solution and MeCN as eluents.

Step B

The obtained intermediate was dissolved in a 1:1 mixture of dioxane andwater (25 mL/mmol) and 10 eq. LiOH×H₂O was added. The mixture wasstirred at r.t. until no further conversion was observed. Then it wasdiluted with brine, neutralized with 2M aqueous HCl, extracted with DCM.The combined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The diastereoisomerswere purified and separated by preparative reversed phase chromatographyusing 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

General Procedure III

1 eq. from the appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative,3 eq. from the appropriate amino acid derivative, 10 mL/mmol DMSO and 4eq. K₂CO₃ were stirred at 150° C. until no further conversion wasobserved. The mixture was acidified with 1M aqueous HCl solution, theprecipitate was filtered and purified via preparative reversed phasechromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

General Procedure IVa

1 eq. from the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative,3 eq. from the appropriate boronic acid derivative, 3 eq. TBAOH, 0.2 eq.palladium acetate, 0.4 eq. tricyclohexylphosphonium tetrafluoroborateand 3.5 mL/mmol DME were stirred under N₂ atmosphere at 120° C. in a MWreactor until no further conversion was observed. Then the mixture wasfiltered through Celite and washed with MTBE and water. The layers wereseparated, the aqueous layer was washed with MTBE. The combined organiclayers were washed with brine, dried over MgSO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via preparative reversed phase chromatography using 40 mMaqueous NH₄OAc (pH=4) solution and MeCN as eluents.

General Procedure IVb

1 eq. from the appropriate 5-iodo-pyrrolo[2,3-d]pyrimidine derivative, 3eq. from the appropriate boronic acid derivative, 3 eq. TBAOH, 0.2 eq.palladium acetate, 0.4 eq. butyldi-1-adamantylphosphine and 7 mL/mmolDME were stirred under N₂ atmosphere at reflux until no furtherconversion was observed. Then the mixture was filtered through Celiteand concentrated under reduced pressure. The residue was purified viaflash chromatography using DCM and MeOH as eluents.

General Procedure V

1 eq. from the appropriate benzofuran-4-ol derivative, 2.5 eq. from theappropriate lactic ester derivative, 2.5 eq. DTAD and 2.5 eq. PPh₃ weredissolved in dry toluene (20 mL/mmol) and stirred at 55° C. until nofurther conversion was observed. Then the mixture was concentrated andthe residue was purified via flash chromatography using heptane andEtOAc as eluents.

General Procedure VI

1 eq. from the appropriate 3-bromo-benzofuran derivative, 2 eq. from theappropriate boronic acid derivative, 2 eq. Cs₂CO₃, 10 mol % Ataphos, 1.5eq. tri-tert-butylphosphonium tetrafluoroborate and THF (10 mL/mmol) andwater (4 mL/mmol) were stirred under N₂ atmosphere at 110° C. in a MWreactor until no further conversion was observed. Then the mixture wasacidified with IM aqueous HCl solution and extracted with DCM. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude product was purified via preparative reversed phase chromatographyusing 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents. The obtainedintermediate was dissolved in dioxane:water 1:1 (10 mL/mmol), 10 eq.LiOH×H₂O was added and the mixture was stirred at r.t. until no furtherconversion was observed. Then the mixture was diluted with water,acidified with IM aqueous HCl solution and extracted with DCM. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents.

Preparation 1a: 5-bromo-4-chloro-6-(4-fluorophenyl)furo[2,3-d]pyrimidineStep A: 2-(4-fluorobenzoyl)propanedinitrile

81 mL IM NaOEt solution in EtOH (81 mmol) was cooled to 0° C. and 6.14 gmalononitrile (93 mmol) was added. The mixture was stirred at 0° C. for1 hour, then 16.8 g 2-bromo-1-(4-fluorophenyl)ethanone (77.4 mmol) wasadded. The mixture was stirred at 0° C. for 1 hour, then at r.t. untilno further conversion was observed. The volatiles were removed underreduced pressure, and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain2-(4-fluorobenzoyl)propanedinitrile. ¹H NMR (400 MHz, CDCl₃): 8.1 (m,2H), 7.24 (m, 2H), 4.41 (t, 1H), 3.75 (d, 2H).

Step B: 2-amino-5-(4-fluorophenyl)furan-3-carbonitrile

6.56 g 2-(4-fluorobenzoyl)propanedinitrile (28.5 mmol) was dissolved in140 mL AcOH and 6 g Amberlite 15H⁺ was added. The mixture was stirred at90° C. until no further conversion was observed. Then the mixture wasfiltered, the filtrate was concentrated under reduced pressure. Theresidue was recrystallized from DCM to obtain2-amino-5-(4-fluorophenyl)furan-3-carbonitrile. 1H NMR (400 MHz,DMSO-d₆): 7.69 (m, 2H), 7.24 (m, 2H), 6.96 (s, 1H)

Step C: 6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one

1290 mg 2-amino-5-(4-fluorophenyl)furan-3-carbonitrile (6.38 mmol) and25.5 mL acetic formic anhydride were placed in a flask and stirred atr.t. for 30 minutes. Then, the volatiles were evaporated under reducedpressure. The residue was dissolved in 51 mL AcOH and heated in a MWreactor at 160° C. for 30 minutes, then at 180° C. for 15 minutes. Thenthe mixture was cooled to r.t., and the precipitate was filtered toobtain 6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one. ¹H NMR (500MHz, DMSO-d₆): 12.66 (br s, 1H), 8.15 (s, 1H), 7.99 (m, 2H), 7.47 (s,1H), 7.33 (m, 2H)

Step D: 5-bromo-6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one

1704 mg 6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one (7.4 mmol) wasdissolved in 74 mL AcOH, then 1182 mg bromine (7.4 mmol) was added. Themixture was stirred at r.t. until no further conversion was observed.The mixture was then filtered, the filtrate was concentrated underreduced pressure. The residue was digerated with 15 mL MeOH, filteredand dried on air to obtain5-bromo-6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one. MS:(M−H)⁺=309.0

Step E: Preparation 1a

1680 mg 5-bromo-6-(4-fluorophenyl)-3H-furo[2,3-d]pyrimidin-4-one (5.44mmol) was dissolved in 12.7 mL POCl₃ (136 mmol) and 690 μL DMA (5.44mmol) was added. The mixture was stirred at 110° C. until no furtherconversion was observed. The mixture was then cooled to 0° C. and pouredinto ice-water. The crude product was isolated by filtration andpurified via flash chromatography using heptane and EtOAc as eluents toobtain Preparation 1a. 1H NMR (400 MHz, DMSO-d₆): 8.87 (s, 1H), 8.16 (m,2H), 7.47 (m, 2H) Preparation 1b:5-bromo-4-chloro-6-ethyl-7H-pyrrolo[2,3-d]pyrimidine

Step A: 6-amino-5-[(2-ethyl-1,3-dioxolan-2-yl)yl)methyl]pyrimidin-4-ol

257 mg6-amino-5-[(2-ethyl-1,3-dioxolan-2-yl)methyl]-2-sulfanyl-pyrimidin-4-ol(0.1 mmol), 0.77 mL aqueous cc. NH₃ solution, 768 mg Raney-Ni and 11 mLwater were placed in a flask under N₂ atmosphere and heated to refluxuntil no further conversion was observed. The warm reaction mixture wasthen filtered through Celite and washed with warm water. The filtratewas concentrated under reduced pressure. The crude product(6-amino-5-[(2-ethyl-1,3-dioxolan-2-yl)methyl]pyrimidin-4-ol) was usedwithout further purification.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.44 (br s, 1H), 7.70 (s, 1H), 6.07 (s,2H), 3.89 (m, 4H), 2.62 (s, 2H), 1.53 (m, 2H), 0.81 (t, 3H)

MS (M+H): 226.2

Step B: 6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol

4.193 g 6-amino-5-[(2-ethyl-1,3-dioxolan-2-yl)methyl]pyrimidin-4-ol(18.6 mmol) was dissolved in 280 mL 0.2M aqueous HCl solution. Themixture was stirred at r.t. until no further conversion was observed.The precipitate was filtered, washed with water and dried to obtain6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol.

1H NMR (400 MHz, DMSO-d₆) δ: 11.67 (s, 1H), 7.75 (s, 1H), 6.12 (t, 1H),2.56 (m, 2H), 1.21 (t, 3H)

MS (M+H): 164.2

Step C: 5-bromo-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol

1.63 g 6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (10 mmol) was dissolvedin 20 mL DMF and cooled to 0° C. 1 mL bromine (20 mmol) was added andthe mixture was stirred at r.t. until no further conversion wasobserved. Then it was diluted with water and aqueous Na₂SO₃ solution andextracted with DCM. The combined organic layers were washed with brine,dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure to obtain5-bromo-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol. 1H NMR (400 MHz,DMSO-d₆) δ: 12.08 (s, 1H), 11.83 (s, 1H), 7.80 (d, 1H), 2.60 (q, 2H),1.16 (t, 3H) MS (M+H): 243.8

Step D: Preparation 1b

1936 mg 5-bromo-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (8 mmol), 4.5 mLPOCl₃ and 969 mg N,N-dimethylaniline (8 mmol) were placed in a flask andstirred at 100° C. until no further conversion was observed. The mixturewas then poured into ice-water and extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure to obtainPreparation 1b.

1H NMR (400 MHz, CDCl₃) δ: 9.79 (s, 1H), 8.59 (s, 1H), 2.91 (q, 2H),1.37 (t, 3H)

MS (M+H): 260.0

Preparation 1c: 3-bromo-2-(4-fluorophenyl)benzofuran-4-ol Step A:2-(4-fluorophenyl)benzofuran-4-ol

2.37 g 2-bromoresorcinol (12.5 mmol) was dissolved in 30 mL dry THFunder N₂ atmosphere and 4.17 mL TEA (30 mmol) and 1.92 mL AcCl (27 mmol)were added respectively. After stirring the mixture for 5 minutes, 2.4 g1-ethynyl-4-fluorobenzene (20 mmol), 561 mg Pd(OAc)₂ (2.5 mmol), 1.45 gtri-tert-butylphosphonium tetrafluoroborate (5 mmol), 476 mg CuI (2.5mmol) and 10 mL dry DIPA were added and the mixture was stirred at 80°C. until no further conversion was observed. Then 2 g LiOH×H₂O was addedand the mixture was stirred at 80° C. until no further conversion wasobserved. The mixture was then concentrated under reduced pressure andpurified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents to obtain2-(4-fluorophenyl)benzofuran-4-ol. 1H NMR (400 MHz, DMSO-d₆) δ: 10.00(s, 1H), 7.91 (m, 2H), 7.38 (s, 1H), 7.31 (t, 2H), 7.10 (t, 1H), 7.04(d, 1H), 6.63 (dd, 1H)

Step B: [2-(4-fluorophenyl)benzofuran-4-yl] acetate

456 mg 2-(4-fluorophenyl)benzofuran-4-ol (2 mmol) was dissolved in 10 mLdry THF then 156 μL AcCl (2.2 mmol) and then 306 μL TEA (2.2 mmol) wereadded carefully. The mixture was stirred under N₂ atmosphere until nofurther conversion was observed. The solvent was then removed underreduced pressure, and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain [2-(4-fluorophenyl)benzofuran-4-yl] acetate. 1H NMR (400 MHz, CDCl₃) δ: 7.84 (m, 2H), 7.42(d, 1H), 7.28 (t, 1H), 7.15 (t, 2H), 7.02 (d, 1H), 6.86 (s, 1H), 2.42(s, 3H)

Step C: [3-bromo-2-(4-fluorophenyl)benzofuran-4-yl] acetate

688 mg [2-(4-fluorophenyl)benzofuran-4-yl] acetate (2.54 mmol) and 589mg NBS (3.31 mmol) were dissolved in 20 mL MeCN and stirred at 70° C.until no further conversion was observed. The solvent was then removedunder reduced pressure, and the residue was purified via flashchromatography using heptane and EtOAc as eluents to obtain[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl] acetate. 1H NMR (400 MHz,CDCl₃) δ: 8.11 (m, 2H), 7.44 (dd, 1H), 7.34 (t, 1H), 7.19 (m, 2H), 7.00(dd, 1H), 2.45 (s, 3H)

Step D: Preparation 1c

175 mg [3-bromo-2-(4-fluorophenyl)benzofuran-4-yl] acetate (0.5 mmol)and 150 μL 1M NaOEt in EtOH solution and 5 mL EtOH were stirred at r.t.under N₂ atmosphere until no further conversion was observed. Themixture was diluted with 50 mL aqueous cc. NH₄Cl solution and extractedwith DCM. The combined organic phases were dried over Na₂SO₄, filteredand the filtrate was concentrated to give Preparation 1c. ¹H NMR (400MHz, DMSO-d₆) δ: 10.16 (br s, 1H), 8.08 (m, 2H), 7.38 (m, 2H), 7.17 (t,1H), 7.08 (d, 1H), 6.70 (d, 1H) Preparation 1d:3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol

Step A: 5-fluoro-2-iodo-benzene-1,3-diol

3.81 g (29.7 mmol) 5-fluorobenzene-1,3-diol was dissolved in 600 mLwater and 8.08 g (31.8 mmol) iodine was added at 0° C. and the mixturewas stirred for 30 minutes. Then pH was adjusted to 3 with NaHCO₃solution and the mixture was stirred until no further conversion wasobserved. Then pH was adjusted to 8 (with NaHCO₃ solution), 20 g Na₂SO₃was added and the mixture was extracted with EtOAc. Combined organicphases were dried over Na₂SO₄, filtered and the filtrate wasconcentrated and purified via flash chromatography using heptane andEtOAc as eluents to obtain 5-fluoro-2-iodo-benzene-1,3-diol. 1H NMR (400MHz, DMSO-d₆): 10.54 (s, 2H), 6.19 (d, 2H)

Step B: (3-acetoxy-5-fluoro-2-iodo-phenyl) acetate

4.78 g 3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol (18.8 mmol)was dissolved in 150 mL THF and 5.70 g TEA (56.5 mmol) was added, then4.267 g Ac₂O (41.4 mmol) was added dropwise at r.t. The mixture wasstirred until no further conversion was observed. The mixture was thenconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain(3-acetoxy-5-fluoro-2-iodo-phenyl) acetate. 1H NMR (400 MHz, DMSO-d₆):7.24 (d, 2H), 2.34 (s, 6H)

Step C: 6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol

5.9 g (3-acetoxy-5-fluoro-2-iodo-phenyl) acetate (17.45 mmol) wasdissolved in 70 mL dry THF and 70 mL dry DIPA under N₂ atmosphere, then3.77 g 1-ethynyl-4-fluorobenzene (31.4 mmol), 587 mg Pd(OAc)₂ (2.62mmol), 1.52 g tri-tert-butylphosphonium tetrafluoroborate (5.24 mmol),and 500 mg CuI (2.62 mmol) were added and the mixture was stirred at 60°C. until no further conversion was observed. Then 2.93 g LiOH×H₂O wasadded and the mixture was stirred at 60° C. until no further conversionwas observed. The mixture was then concentrated under reduced pressureand purified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents to obtain6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol. 1H NMR (400 MHz, DMSO-d₆):10.60 (s, 1H), 7.89 (m, 2H), 7.38 (s, 1H), 7.32 (m, 2H), 6.99 (m, 1H),6.48 (dd, 1H)

Step D: [6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate

2.49 mg 6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol (10.1 mmol) wasdissolved in 50 mL dry THF then 791 μL AcCl (11.1 mmol) and then 1.55 mLTEA (11.1 mmol) were added carefully. The mixture was stirred under N₂atmosphere until no further conversion was observed. The solvent wasthen removed under reduced pressure, the residue was purified via flashchromatography using heptane and EtOAc as eluents to obtain[6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate. 1H NMR (400 MHz,DMSO-d₆): 7.95 (m, 2H), 7.57 (m, 1H), 7.46 (s, 1H), 7.37 (m, 2H), 7.09(dd, 1H), 2.40 (s, 3H)

Step E: [3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate

2.96 g [6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate (10.27 mmol)and 2.28 g NBS (12.84 mmol) were dissolved in 120 mL MeCN and stirred at60° C. until no further conversion was observed. The solvent was thenremoved under reduced pressure, the residue was purified via flashchromatography using heptane and EtOAc as eluents to obtain[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate. 1H NMR(400 MHz, DMSO-d₆): 8.07 (m, 2H), 7.69 (dd, 1H), 7.44 (m, 1H), 7.19 (m,2H), 7.09 (dd, 1H), 2.41 (s, 3H)

Step F: Preparation 1d

3.35 g [3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate(9.12 mmol) and 8.67 mL IM NaOEt in EtOH solution and 90 mL EtOH werestirred at r.t. under N₂ atmosphere until no further conversion wasobserved. The mixture was diluted with 50 mL aqueous cc. NH₄Cl solutionand extracted with DCM. The combined organic phases were dried overNa₂SO₄, filtered and the filtrate was concentrated to give Preparation1d. ¹H NMR (400 MHz, DMSO-d₆): 10.78 (s, 1H), 8.06 (m, 2H), 7.40 (m,2H), 7.06 (dd, 1H), 6.54 (dd, 1H)

Preparation 2a: Ethyl (2R)-2-acetoxy-3-(2-hydroxyphenyl)propanoate andPreparation 2b: Ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyl)propanoate StepA: [2-(Bromomethyl)phenyl]acetate

60.07 g 2-methylphenyl acetate (400 mmol) and 106.8 g NBS (600 mmol)were placed in a 1 L flask. 500 mL cyclohexane was added, and then withintensive stirring 3.284 g AIBN (20 mmol) was added over 30 minutes. Themixture was stirred at 80° C. until no further conversion was observed,then cooled to r.t. The precipitate was filtered off and washed withcyclohexane. The mother liquor was concentrated under reduced pressure,and the crude product was used in Step B without further purification.

Step B: Preparations 2a and 2b

23.10 g anhydrous LiCl (545 mmol) and 65.36 g anhydrous ZnCl₂ (479.6mmol) were placed in a 2 L flask, then dried at 160° C. under 0.1 mmHgfor 1 hour. After cooling to r.t. under argon atmosphere, 26.49 gmagnesium turnings (1090 mmol) and 1 L dry pre-cooled (0° C.) THF wereadded. The resulting mixture was immersed into an ice-bath, and thenstirred for 30 minutes. 100 g [2-(bromomethyl)phenyl] acetate (crudeproduct from Step A, ˜436 mmol) was dissolved in 120 mL dry THF and wasadded to the precooled inorganics over 15 minutes. After addition of thereagent the resulting mixture was stirred for 45 minutes while keepingthe temperature between 0-5° C. Then 64.82 mL ethyl 2-oxoacetate (654mmol, 50% in toluene) was added over 5 minutes and the resulting mixturewas stirred for another 15 minutes. The remaining inorganics wereremoved by filtration, and the filtrate was diluted with 500 mL MeOH. Itwas stirred until the intramolecular acetyl group migration from thephenolic oxygen to the alkyl oxygen was complete. Then 30 mL acetic acidwas added the volatiles were evaporated under reduced pressure. 350 mLwater was added to the residue and it was extracted with EtOAc. Thecombined organic layers were washed with saturated aqueous NaHCO₃ andwith brine, and then dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. Then 100 mL hexane was added and itwas stirred for 30 minutes at 0° C. The formed white crystals werecollected by filtration and washed with hexane. 1H NMR (500 MHz,DMSO-d₆) δ: 9.53 (s, 1H), 7.06 (t, 1H), 7.04 (d, 1H), 6.79 (d, 1H), 6.71(t, 1H), 5.10 (dd, 1H), 4.05 (q, 2H), 3.06 (dd, 1H), 2.94 (dd, 1H), 2.00(s, 3H), 1.09 (t, 3H)

The enantiomers were separated via chiral chromatography. Column: OD;Eluents: heptane/EtOH; the enantiomer eluting earlier was collected asPreparation 2b with 99.8% ee and the enantiomer eluting later wascollected as Preparation 2a with 99.9% ee.

Preparation 2c: Ethyl(2R)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoateStep A:(2R)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoicAcid

30.3 g Preparation 2a (120 mmol), 38.9 g Preparation 5b (180 mmol) and47.2 g triphenyl phosphine (180 mmol) were dissolved in 120 mL drytoluene, then 82 mL DEAD (180 mmol, 40% in toluene) was added. Themixture was stirred at 50° C. under nitrogen atmosphere until no furtherconversion was observed. The volatiles were evaporated under reducedpressure. Then 300 mL DEE was added, the mixture was sonicated andfiltered, washed with DEE. The filtrate was concentrated under reducedpressure. The residue was dissolved in 125 mL THF, then 24 g NaOH (0.6mol) dissolved in 125 mL water was added. The mixture was stirred at 50°C. until no further conversion was observed. The pH was set to 5 withcc. HCl, and the volatiles were removed under reduced pressure. 100 mLwater and 350 mL DCM were added, the mixture was stirred at 0° C. andthe precipitate was filtered, washed with cold water and DCM and driedunder reduced pressure to obtain(2R)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoicacid. ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.88 (d, 1H), 7.80 (d, 1H), 7.55 (dd,1H), 7.49-7.44 (m, 1H), 7.26 (dd, 1H), 7.17-7.11 (m, 2H), 7.06 (t, 1H),6.98 (d, 1H), 6.88 (t, 1H), 5.22 (s, 2H), 4.50 (d, 1H), 3.81 (dd, 1H),3.77 (s, 3H), 3.73 (dd, 1H), 2.44 (dd, 1H)

Step B: Preparation 2c

51.7 g (2R)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid (136 mmol) was dissolved in 520 mL EtOH,then 20 mL cc. H₂SO₄ was added. The mixture was stirred at 60° C. untilno further conversion was observed. Then it was diluted with water,neutralized with aqueous saturated NaHCO₃ solution and extracted withdichloromethane. The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure andpurified via flash chromatography using EtOAc and MeOH as eluents toobtain Preparation 2c. HRMS calculated for C₂₃H₂₄N₂O₅: 408.1685, found:409.1757 (M+H).

Preparation 2d: Ethyl(2S)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

Preparation 2d was synthesized the way as Preparation 2c, but startingfrom Preparation 2b instead of Preparation 2a.

Preparation 2e: Ethyl (2R)-2-hydroxy-3-(2-methoxyphenyl)propanoate andPreparation 2f: Ethyl (2S)-2-hydroxy-3-(2-methoxyphenyl)propanoate

The enantiomers of ethyl 2-hydroxy-3-(2-methoxyphenyl)propanoate wereseparated via chiral chromatography; Column: AD, Eluent: 2-PrOH; theenantiomer eluting earlier was collected as Preparation 2e with 99.8%ee. The enantiomer eluting later was collected as Preparation 2f with97.8% ee.

Preparation 2g: Ethyl(2R)-2-hydroxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate Step A: Ethyl(2R)-2-acetoxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate

1 eq. Preparation 2a, 2 eq. of pyrazin-2-ylmethanol and 2 eq.triphenylphosphine were dissolved in dry toluene (0.2M for the phenol),then 2 eq. DTAD was added. The mixture was stirred at 50° C. undernitrogen atmosphere. After reaching an appropriate conversion thevolatiles were removed under reduced pressure. The crude intermediatewas purified via flash chromatography using heptane and EtOAc as eluentsto obtain ethyl(2R)-2-acetoxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate.

Step B: Preparation 2g

Ethyl (2R)-2-acetoxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate wasdissolved in ethanol (0.5M) then 2 mol % NaOEt solution (1.0M inethanol) was added. The resulting mixture was stirred at r.t. AdditionalNaOEt solution was added if conversion was not complete. The mixture wasconcentrated to half of its volume, then water and brine was added, andit was extracted with EtOAc. The combined organics were dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingDCM and methanol as eluents to obtain Preparation 2g. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.88 (s, 1H), 8.64 (dd, 2H), 7.22-7.16 (m, 2H), 7.06 (d,1H), 6.89 (t, 1H), 5.46 (d, 1H), 5.27 (dd, 2H), 4.29 (dq, 1H), 4.00 (q,2H), 3.09 (dd, 1H), 2.79 (dd, 1H), 1.08 (t, 3H)

Preparation 2h: Ethyl(2S)-2-hydroxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate Step A:Ethyl (2S)-2-hydroxy-3-(2-hydroxyphenyl)propanoate

13.633 g Preparation 2b (54 mmol) was dissolved in 200 mL dry EtOH, then30 mL NaOEt solution (IM in EtOH) was added and the mixture was stirredat r.t. If needed, the addition of the NaOEt solution was repeated untilthe cleavage of the acetyl group was complete. The mixture was dilutedwith 600 mL water and it was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The obtained ethyl(2S)-2-hydroxy-3-(2-hydroxyphenyl)propanoate was used in the next stepwithout further purification.

Step B: Preparation 2h

9.18 g ethyl (2S)-2-hydroxy-3-(2-hydroxyphenyl)propanoate (43.7 mmol)was dissolved in 130 mL dry DMF, then 6.040 g K₂CO₃ (43.7 mmol) wasadded. After 5 minutes stirring 7.7 mL 2,2,2-trifluoroethyltrifluoromethanesulfonate (48 mmol) was added over 5 minutes. Theresulting mixture was stirred until no further conversion was observed.The reaction mixture was diluted with brine, then extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via flash chromatography using heptane and EtOAc as eluents. 1HNMR (500 MHz, DMSO-d₆) δ: 7.23 (t, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95(t, 1H), 5.50 (d, 1H), 4.75 (q, 2H), 4.22 (m, 1H), 4.02 (q, 2H), 3.00(dd, 1H), 2.76 (dd, 1H), 1.09 (t, 3H)

Preparation 2i:(2R)-2-amino-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoicAcid Step A: ethyl (2R)-2-amino-3-(2-hydroxyphenyl)propanoatehydrochloride

653 mg (2R)-2-amino-3-(2-hydroxyphenyl)propanoic acid hydrochloride (3.0mmol) was dissolved in 6 mL HCl (1.25 M in EtOH) and stirred at 60° C.until no further conversion was observed. Then the reaction mixture wascarefully diluted with 10% aqueous NaHCO₃ solution and extracted withDCM. The combined organic phase was dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The product should bestored in freezer.

¹H NMR (500 MHz, DMSO-d₆) δ: 7.05-6.95 (m, 2H), 6.72 (dm, 1H), 6.69-6.63(m, 1H), 4.02 (q, 2H), 3.65 (dd, 1H), 2.84 (dd, 1H), 2.78 (dd, 1H), 1.12(t, 3H) HRMS calculated for C₁₁H₁₅NO₃: 209.1052; found: 210.1128 (M+H).

Step B: ethyl(2R)-2-amino-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

3.96 g ethyl (2R)-2-amino-3-(2-hydroxyphenyl)propanoate hydrochloride(18.9 mmol) was dissolved in 200 mL dry toluene, then 5.69 g PPh₃ (21.7mmol), 4.69 g Preparation 5b (21.7 mmol) were added and the mixture washeated to 35° C., then 5.0 g DTAD (21.7 mmol) was added and the mixturewas stirred at 45° C. until no further conversion was observed. Then themixture was concentrated under reduced pressure and purified via flashchromatography using EtOAc and MeOH as eluents.

¹H NMR (500 MHz, DMSO-d₆) δ: 8.92 (d, 1H), 7.61 (d, 1H), 7.55 (dd, 1H),7.46 (td, 1H), 7.20 (td, 1H), 7.17 (dd, 1H), 7.15 (dd, 1H), 7.06 (td,1H), 7.04 (dd, 1H), 6.91 (td, 1H), 5.27/5.23 (d, 2H), 4.01 (q, 2H), 3.76(s, 3H), 3.68 (dd, 1H), 3.08 (br, 2H), 3.03/2.83 (dd, 2H), 1.07 (t, 3H)

HRMS calculated for C₂₃H₂₅N₃O₄: 407.1845; found: 408.1928 (M+H).

Step C: Preparation 2i

3.20 g ethyl(2R)-2-amino-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(7.85 mmol) was dissolved in 10 mL THF, then 10 mL water and 420 mgLiOH×H₂O (10 mmol) were added and the mixture was stirred at r.t. untilthe hydrolysis was complete. Then it was diluted with water andneutralized with 2 M aqueous HCl solution. The formed precipitate wasfiltered, washed with water and dried to obtain Preparation 2i.

1H NMR (500 MHz, DMSO-d₆) δ: 8.88 (d, 1H), 7.82 (d, 1H), 7.54 (dd, 1H),7.47 (m, 1H), 7.27 (dd, 1H), 7.23 (t, 1H), 7.16 (d, 1H), 7.06 (t, 1H),7.05 (d, 1H), 6.93 (t, 1H), 5.26 (s, 2H), 3.76 (s, 3H), 3.59 (dd, 1H),3.49/2.83 (dd, 2H) HRMS calculated for C₂₁H₂₁N₃O₄: 379.1532; found:380.1610 (M+H).

Preparation 3a:2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenolStep A: (4-Bromo-2-chloro-phenoxy)-trimethyl-silane

20.8 g 4-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 mL dryTHF then 24.2 g HMDS (150 mmol) was added. The reaction mixture wasstirred at 85° C. under argon atmosphere for 1.5 hours then concentratedunder reduced pressure. The resulted crude product was used withoutfurther purification. 1H NMR (200 MHz, CDCl₃): 7.49 (d, 1H), 7.23 (dd,1H), 6.75 (d, 1H), 0.26 (s, 9H)

Step B: 4-Bromo-2-chloro-3-methyl-phenol

48 mL ^(n)BuLi solution in hexanes (120 mmol, 2.5M in hexanes) was addeddropwise to a solution of 12.1 g dry DIPA (120 mmol) in 250 mL dry THFat −78° C. under argon atmosphere. The mixture was stirred for 30minutes at the same temperature then 28.0 g(4-bromo-2-chloro-phenoxy)-trimethyl-silane (100 mmol) was addeddropwise. After 2.5 hours, 21.3 g MeI (150 mmol) was added dropwise thenthe cooling bath was removed and the mixture was stirred overnight. Thereaction was quenched with 100 mL aqueous NH₃ solution and 200 mLsaturated aqueous NH₄Cl solution and extracted with EtOAc. The organicphase was dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The resulting dark mass was refluxed with purehexane several times (150-150 mL aliquots) and decanted leaving a blacktar behind. The combined organic phases were concentrated under reducedpressure affording 19.0 g crude product, which was used without furtherpurification. 1H NMR (200 MHz, CDCl₃) δ: 7.32 (d, 1H), 6.76 (d, 1H),5.62 (s, 1H), 2.49 (s, 3H)

Step C: (4-Bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane

20.8 g HMDS (129 mmol) was added to the solution of 19.0 g4-bromo-2-chloro-3-methyl-phenol (86.0 mmol) in 150 mL dry THF. Themixture was stirred at 85° C. under argon balloon for 1.5 hours and thenconcentrated under reduced pressure. The obtained product was usedwithout further purification. 1H NMR (200 MHz, CDCl₃) δ: 7.30 (d, 1H),6.63 (d, 1H), 2.50 (s, 3H), 0.28 (s, 9H)

Step D: Preparation 3a

A solution of 25.2 g(4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (86.0 mmol) in 250mL dry THF was cooled to −78° C. under argon and then 38 mL ^(n)BuLisolution (94.6 mmol, 2.5M in hexanes) was added dropwise. After 5minutes, 19.2 g 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(103 mmol) was added dropwise. The cooling bath was removed and themixture was slowly allowed to warm up to r.t. Then the mixture was addedto 200 mL saturated aqueous NH₄Cl solution and extracted with EtOAc. Thecombined organic layers were concentrated under reduced pressure andpassed through a pad of silica gel using hexane and EtOAc as eluents.The crude product was recrystallized from a mixture of EtOAc and hexaneto obtain Preparation 3a. 1H NMR (500 MHz, DMSO-d₆) δ: 10.40 (s, 1H),7.42 (d, 1H), 6.80 (d, 1H), 2.49 (s, 3H), 1.27 (s, 12H)

Preparation 3b:1-[2-[2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine

10.0 g Preparation 3a (37.2 mmol), 8.7 g2-(4-methylpiperazin-1-yl)ethanol (60.3 mmol) and 15.8 g PPh₃ (60.3mmol) were dissolved in 100 mL dry toluene and then 27 mL DEAD (60.3mmol, 40% solution in toluene) was added dropwise. The mixture wasstirred at 50° C. under argon atmosphere until no further conversion wasobserved. The volatiles were evaporated under reduced pressure and 100mL Et₂O was added. The precipitated white crystals were filtered off andwashed with Et₂O. The filtrate was concentrated under reduced pressureand purified via flash chromatography using CHCl₃ and MeOH as eluents.The resulting light brown oil was crystallized from hexane to givePreparation 3b as an off-white solid. 1H NMR (500 MHz, DMSO-d₆) δ: 7.56(d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50(br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)

Preparation 3c:2-(3-chloro-2-methyl-phenyl)-5,5-dimethyl-1,3,2-dioxaborinane

4.94 g (3-chloro-2-methylphenyl)boronic acid (29 mmol) and 3.021 gneopentyl-glycol (29 mmol) were stirred at r.t. in the presence ofAmberlite 15H⁺ (dried with toluene) until no further conversion wasobserved. The mixture was then filtered through Celite and washed with2-Me-THF. The filtrate was concentrated under reduced pressure to obtainPreparation 3c. ¹H NMR (400 MHz, CDCl₃): 7.59 (dd, 1H), 7.38 (dd, 1H),7.10 (t, 1H), 3.79 (s, 4H), 2.57 (s, 3H), 1.05 (s, 6H)

Preparation 4: Ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate

Using General procedure 1a and Preparation 2c as the appropriate lacticester derivative, Preparation 4 was obtained. MS: (M+H)⁺=700.4

Preparation 5a: (E)-4-(Dimethylamino)-1,1-dimethoxy-but-3-en-2-one

502.1 g 1,1-dimethoxypropan-2-one (4.25 mol) and 506.4 g1,1-dimethoxy-N,N-dimethyl-methanamine (4.25 mol) were mixed in a 2 Lflask and stirred at 105° C. for 3 hours. The formed MeOH was removedcontinuously via distillation. When MeOH formation stopped (at 65° C.head temperature) the reaction mixture was vacuum distilled (decreasingthe pressure slowly to 30 mbar) to remove side products and unreactedstarting materials. The crude product was distilled at 0.1 mbar.Fractions were collected between 107-118° C. head temperature (bathtemperature 160-165° C.) to give a yellow oil. ¹H NMR (500 MHz, DMSO-d₆)δ: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H),2.78 (s, 3H)

Preparation 5b: [2-(2-Methoxyphenyl)pyrimidin-4-yl]methanol Step A:4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine

To the mixture of 1.2 eq. 2-methoxybenzamidine acetic acid salt and 1eq. Preparation 5a in dry methanol (0.5 mL/mmol), 1.2 eq. NaOEt wasadded portionwise and the mixture was stirred at 75° C. until no furtherconversion was observed. Then the reaction mixture was cooled andconcentrated under reduced pressure. Water was added to the residue andit was extracted with DCM. The combined organic layers were dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and EtOAc as eluents to give4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine. 1H NMR (400 MHz,DMSO-d₆) δ: 8.93 (d, 1H), 7.55-7.44 (m, 3H), 7.16 (d, 1H), 7.06 (m, 1H),5.31 (s, 1H), 3.76 (s, 3H), 3.37 (s, 6H)

Step B: Preparation 5b

261 mg 4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine (1.0 mmol) wasdissolved in 2 mL HCl in dioxane (4M solution), then 2 mL water wasadded and this mixture was stirred at 50° C. for 16 hours. The reactionmixture was cooled to 0° C., then 320 mg NaOH (8.0 mmol) was addedportionwise. The pH was adjusted to 8 using 10% aqueous K₂CO₃ solution,then 76 mg sodium borohydride (2.0 mmol) was added and the mixture wasstirred for 30 minutes at 0° C. The reaction mixture was diluted with 5mL water and extracted with EtOAc. The combined organic phases weredried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents to give Preparation5b. 1H NMR (400 MHz, DMSO-d₆) δ: 8.84 (d, 1H), 7.50-7.42 (m, 3H), 7.14(d, 1H), 7.03 (m, 1H), 5.66 (t, 1H), 4.58 (d, 2H), 3.75 (s, 3H)

Preparation 6:(2R)-2-[(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoic Acid Step A:7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine

255 mg NaH (6.38 mmol) and 50 mL dry THF were charged into a 50 mLSchlenk tube under N₂ atmosphere and the slurry was cooled to 0° C. Then1.792 g Preparation 1b (5.8 mmol) was added. After stirring the mixturefor 30 minutes at 0° C., 773 μL benzyl bromide (6.38 mmol) was added andthe mixture was allowed to warm up to r.t., and stirred until no furtherconversion was observed. The mixture was then diluted with saturatedaqueous NH₄Cl solution, and extracted with DCM. The combined organiclayers were washed with brine, dried over MgSO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via flash chromatography using heptane and EtOAc as eluents toobtain 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.60 (s, 1H), 7.33-7.26 (m, 3H), 7.06-7.04(m, 2H), 5.54 (s, 2H), 2.79 (q, 2H), 1.07 (t, 3H)

MS (M+H): 351.8

Step B: Preparation 6

Using General Procedure III and7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative, Preparation 6was obtained.

MS (M+H): 279.2

Preparation 7a:N-[2-benzyloxy-6-(2,2-dibromovinyl)phenyl]-3-chloro-2-methyl-4-triisopropylsilyloxy-anilineStep A: (4-Bromo-2-chloro-phenoxy)-triisopropyl-silane

200 g 4-bromo-2-chloro-phenol (0.97 mol) and 126 mL TIPSCl (1.18 mol)were dissolved in 1.6 L DCM. 167 g imidazole (2.45 mol) was added andthe mixture was stirred at r.t. for 2 hours. Then the volatiles wereevaporated under reduced pressure and the residue was dissolved in 1.5 LEtOAc. The mixture was washed with brine, dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. Thetriisopropylsilyl hydroxide impurity was removed by distillation (120°C. at 0.01 mmHg). The residue was filtered through a short pad of silicawith hexane and concentrated under reduced pressure. The product(colourless oil) was used in the next step without further purification.

1H NMR (400 MHz, CDCl₃) δ: 7.49 (d, 1H), 7.21 (dd, 1H), 6.78 (d, 1H),1.31 (septet, 3H), 1.14 (d, 18H)

MS (EI, 70 eV) m/z (% relative intensity, [ion]): 63 (30), 79 (24), 93(41), 170 (17), 235 (19), 251 (16), 265 (24), 293 (23), 319 (77), 321(100), 323 (28), 362 (1, [M⁺])

Step B: (4-Bromo-2-chloro-3-methyl-phenoxy)-triisopropyl-silane

76.0 mL dry DIPA (0.54 mol) was dissolved in 1.2 L dry THF under argonatmosphere and 51.2 mL ^(n)BuLi solution (0.512 mol, 10M in hexanes) wasadded dropwise at −78° C. The mixture was stirred for 45 minutes at thesame temperature. Then 178 g(4-bromo-2-chloro-phenoxy)-triisopropyl-silane (0.488 mol) was addeddropwise at −78° C. and the white suspension was stirred until nofurther conversion was observed. Then 36.5 mL MeI (0.586 mmol) was addedat this temperature and the reaction mixture was stirred overnightwithout further cooling. The volatiles were evaporated under reducedpressure. The residue was dissolved in 1.5 L EtOAc, washed with brine.The organic phase was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was filteredthrough a short pad of silica using hexane as eluent and concentratedunder reduced pressure to obtain the product as pale yellow oil. 1H NMR(400 MHz, CDCl₃) δ: 7.30 (d, 1H), 6.68 (d, 1H), 2.53 (s, 3H), 1.32(septet, 3H), 1.14 (d, 18H)

Step C: N-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxy-aniline

7.56 g (4-bromo-2-chloro-3-methyl-phenoxy)-triisopropyl-silane (20 mmol)and 4.29 g benzylamine (40 mmol) were dissolved in 16 mL dry toluene,then 450 mg Pd₂dba₃ (0.5 mmol), 450 mg X-Phos (1 mmol) and 9.77 g Cs₂CO₃(30 mmol) were added and the mixture was stirred at 100° C. until nofurther conversion was observed. Then it was filtered through Celite,and the filtrate was concentrated under reduced pressure. The crudeproduct was purified via flash chromatography using hexane and EtOAc aseluents to obtainN-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxy-aniline.

Step D: 3-chloro-2-methyl-4-triisopropylsilyloxy-aniline

3.50 g N-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxy-aniline (8.66mmol) was dissolved in 100 mL MeOH and 20 mL EtOAc, then 80 mg 10% Pd/Cwas added and the mixture was stirred under 1 bar H₂ atmosphere until nofurther conversion was observed. Then it was filtered through Celite,and the filtrate was concentrated under reduced pressure. The crudeproduct was purified via flash chromatography using hexane and EtOAc aseluents to obtain 3-chloro-2-methyl-4-triisopropylsilyloxy-aniline.

1H NMR (400 MHz, DMSO-d₆) δ: 6.58 (d, 1H), 6.50 (d, 1H), 4.68 (s, 2H),2.11 (s, 3H), 1.24 (m, 3H), 1.06 (d, 18H)

MS: (M+H)⁺=314.2

Step E: 3-benzyloxy-2-bromo-benzaldehyde

4.554 g 2-bromo-3-hydroxybenzaldehyde (22.65 mmol), 4.262 g benzylbromide (24.92 mmol) and 4.696 g K₂CO₃ (33.98 mmol) were dissolved in 20mL DMSO and stirred at 50° C. until no further conversion was observed.The mixture was then poured into water. The precipitate was filtered togive 3-benzyloxy-2-bromo-benzaldehyde. MS (EI, 70 eV) m/z (% relativeintensity, [ion]): 65 (10), 91 (100), 290 (5, [M⁺]), 292 (5, [M⁺])

Step F:3-benzyloxy-2-(3-chloro-2-methyl-4-triisopropylsilyloxy-anilino)benzaldehyde

5.0 g 3-benzyloxy-2-bromo-benzaldehyde (17.17 mmol), 5.391 g3-chloro-2-methyl-4-triisopropylsilyloxy-aniline (17.17 mmol), 16.782 gCs₂CO₃ (51.51 mmol), 393 mg Pd₂dba₃ (0.43 mmol) and 535 mg rac. BINAP(0.86 mmol) were mixed in 85 mL toluene and stirred at 120° C. until nofurther conversion was observed. The volatiles were removed underreduced pressure, the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain3-benzyloxy-2-(3-chloro-2-methyl-4-triisopropylsilyloxy-anilino)benzaldehyde. MS: (M+H)⁺=524.2

Step G: Preparation 7a

7.7 g3-benzyloxy-2-(3-chloro-2-methyl-4-triisopropylsilyloxy-anilino)benzaldehyde(14.69 mmol) and 7.308 g carbon tetrabromide (22.03 mmol) were dissolvedin 160 mL DCM at 0° C., then 11.56 g PPh₃ (44.07 mmol) was added. Themixture was stirred at r.t. until no further conversion was observed.Then the solvent was removed under reduced pressure, the residue wasdissolved in Et₂O. Then heptane was added and the formed precipitate wasfiltered, the filtrate was concentrated under reduced pressure. Thenheptane was added, and the mixture was stirred for 10 minutes andfiltered again. The filtrate was concentrated under reduced pressure andpurified via flash chromatography using heptane and EtOAc as eluents togive Preparation 7a.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.28-7.23 (m, 5H), 7.19 (s, 1H), 7.11 (dd,2H), 7.05 (d, 1H), 6.60 (d, 1H), 6.41 (s, 1H), 6.22 (d, 1H), 5.08 (s,2H), 2.30 (s, 3H), 1.25 (m, 3H), 1.05 (d, 18H)

MS: (M+H)⁺=680.0

Preparation 7b: Ethyl(2R)-2-[1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indol-7-yl]oxy-3-(2-methoxyphenyl)propanoateStep A:[4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenoxy]-triisopropyl-silane

2720 mg Preparation 7a (4 mmol), 1119 mg 4-fluorophenylboronic acid (8mmol), 4245 mg K₃PO₄ (20 mmol), 90 mg Pd(OAc)₂ (0.4 mmol) and 328 mgSPhos (0.8 mmol) were mixed in 60 mL dry toluene under N₂ atmosphere andstirred at 100° C. until no further conversion was observed. Then thesolvent was removed under reduced pressure, the residue was purified viaflash chromatography using heptane and EtOAc as eluents to give[4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenoxy]-triisopropyl-silane.1H NMR (400 MHz, CDCl₃) δ: 7.33 (d, 2H), 7.29-t.22 (m, 2H), 7.18 (d,1H), 7.16 (d, 1H), 7.10 (t, 2H), 6.94 (d, 1H), 6.92-6.84 (m, 4H), 6.73(s, 1H), 6.61 (d, 1H), 4.94 (d, 1H), 4.89 (d, 1H), 1.97 (s, 3H), 1.31(m, 3H), 1.13 (t, 18H)

Step B:4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenol

2600 mg[4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenoxy]-triisopropyl-silane(2.96 mmol), 2.96 mL TBAF solution (2.96 mmol, IM in THF) and 50 mL THFwere stirred at r.t. until no further conversion was observed. Thesolvent was then removed under reduced pressure, the residue waspurified via flash chromatography using heptane and EtOAc as eluents togive4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenol.

¹H NMR (400 MHz, DMSO-d₆) δ: 10.27 (br s, 1H), 7.28-7.18 (m, 6H), 7.10(t, 2H), 7.07-6.99 (m, 2H), 6.85-6.77 (m, 3H), 6.75 (s, 1H), 6.72 (d,1H), 4.95 (d, 1H), 4.90 (d, 1H), 1.75 (s, 3H)

MS: (M+H)⁺=458.0.

Step C:7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole

1.2 g4-[7-benzyloxy-2-(4-fluorophenyl)indol-1-yl]-2-chloro-3-methyl-phenol(2.1 mmol), 606 mg 1-(2-hydroxyethyl)-4-methylpiperazine (4.2 mmol) and2.1 g PPh₃ (6.3 mmol) were dissolved in 50 mL dry toluene under N₂atmosphere and the mixture was cooled to 0° C. Then 1451 mg DTAD (6.3mmol) was added and the mixture was heated to 45° C. and stirred untilno further conversion was observed. The solvent was then removed underreduced pressure, the residue was purified via flash chromatographyusing heptane and EtOAc and MeOH as eluents to give7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole.MS: (M+H)⁺=584.2

Step D:1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indol-7-ol

1280 mg7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole(2.19 mmol) was dissolved in 100 mL EtOH, then 100 mg 10% Pd/C wasadded. The mixture was stirred under 1 bar H₂ atmosphere at r.t. untilno further conversion was observed. Then the mixture was filteredthrough Celite and the filtrate was concentrated to give1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indol-7-ol.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (br s, 1H), 7.25 (dd, 2H), 7.17-7.03(m, 4H), 6.94 (d, 1H), 6.86 (t, 1H), 6.70 (s, 1H), 6.47 (d, 1H), 4.13(m, 2H), 2.72 (t, 2H), 2.58-2.42 (br s, 4H), 2.40-2.17 (br s, 4H), 2.14(s, 3H), 1.86 (s, 3H)

MS: (M+H)⁺=494.2

Step E: Preparation 7b

494 mg1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indol-7-ol (1 mmol), 449 mg Preparation 2f (2 mmol) and 786 mgPPh₃ (3 mmol) were dissolved in 10 mL dry toluene under N₂ atmosphereand the mixture was cooled to 0° C. Then 691 mg DTAD (3 mmol) was addedand the mixture was heated to 45° C. and stirred until no furtherconversion was observed. The solvent was then removed under reducedpressure, the residue was purified via flash chromatography usingheptane and EtOAc and MeOH as eluents to give Preparation 7b as amixture of diastereoisomers.

¹H NMR (500 MHz, DMSO-d₆) δ: 7.43/6.98 (d, 1H), 7.28 (m, 2H), 7.23/7.24(d, 1H), 7.17/7.18 (t, 1H), 7.14 (m, 2H), 7.12/6.88 (d, 1H), 6.95/6.94(t, 1H), 6.91/6.91 (d, 1H), 6.79/6.78 (s, 1H), 6.73/6.75 (t, 1H),6.52/6.60 (d, 1H), 6.46/6.40 (d, 1H), 4.85/4.76 (dd, 1H), 4.25-4.01 (m,2H), 4.01-3.89 (m, 2H), 3.77/3.76 (s, 3H), 2.70-2.60 (m, 3H), 2.54-2.30(m, 5H), 2.21 (br s, 4H), 2.13/2.09 (s, 3H), 1.59/2.08 (s, 3H),0.99/0.98 (t, 3H)

MS: (M+H)⁺=700.0

Example 1:(2R)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid

Using General Procedure II and Preparation 4 as the appropriate5-bromo-furo[2,3-d]pyrimidine derivative and Preparation 3b as theappropriate boronic acid derivative, Example 1 was obtained as a mixtureof diastereoisomers. HRMS calculated for C₄₇H₄₄ClFN₆O₇: 858.2944, found:430.1547 and 430.1555 (M+2H).

Example 2:(2R)-2-{[5-{3-chloro-2-ethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A:1-[2-(4-bromo-2-chloro-phenoxy)ethyl]-4-methyl-piperazine

10.373 g 4-bromo-2-chlorophenol (50 mmol), 14.442 g2-(4-methylpiperazin-1-yl)ethanol (100 mmol) and 26.229 g PPh₃ (100mmol) were dissolved in 250 mL dry toluene under N₂ atmosphere, then23.027 g DTAD (100 mmol) was added. The mixture was stirred at 50° C.until no further conversion was observed. The volatiles were evaporatedunder reduced pressure and the residue was purified via flashchromatography using EtOAc and MeOH as eluents. MS (M+H): 333.0

Step B:1-[2-(4-bromo-2-chloro-3-ethyl-phenoxy)ethyl]-4-methyl-piperazine

2.0 g 1-[2-(4-bromo-2-chloro-phenoxy)ethyl]-4-methyl-piperazine (6 mmol)was dissolved in 50 mL dry THF under N₂ atmosphere and was cooled to−78° C. 6 mL LDA solution (12 mmol in 2M THF) was added and the mixturewas stirred for 3 hours, then 982 mg iodoethane (6.3 mmol) was added andthe mixture was allowed to warm up to r.t. It was quenched withsaturated aqueous NH₄Cl solution, extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. MS (M+H): 360.8

Step C:1-[2-[2-chloro-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine

2099 mg1-[2-(4-bromo-2-chloro-3-ethyl-phenoxy)ethyl]-4-methyl-piperazine (5.8mmol) was dissolved in 30 mL dry THF under N₂ atmosphere and was cooledto −78° C. 4.65 mL ^(n)BuLi solution (11.61 mmol in 2.5M THF) was addeddropwise. It was stirred for 5 hours, then 2.6 mL2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.77 mmol) wasadded and the mixture was stirred for 30 minutes. Then it was allowed towarm up to r.t. and it was concentrated under reduced pressure. Thecrude product was purified via flash chromatography using EtOAc and MeOHas eluents. MS (M+H): 409.2

Step D: Example 2

Using General Procedure II and Preparation 4 as the appropriate5-bromo-furo[2,3-d]pyrimidine derivative and1-[2-[2-chloro-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as the appropriate boronic acid derivative,Example 2 was obtained as a mixture of diastereoisomers. HRMS calculatedfor C₄₈H₄₆ClFN₆O₇: 872.3101, found: 437.1620 and 437.1620 (M+2H).

Example 3:(2R)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic Acid Step A: Ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate

Using General procedure 1a and Preparation 2e as the appropriate lacticester derivative, ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate was obtained. 1H NMR (400 MHz, DMSO-d₆): 8.53 (s, 1H),8.10 (m, 2H), 7.47-7.36 (m, 3H), 7.23 (m, 1H), 6.96 (m, 1H), 6.89 (t,1H), 5.58 (m, 1H), 4.12 (q, 2H), 3.79 (s, 3H), 3.36 (m, 1H), 3.21 (m,1H), 1.11 (t, 3H)

Step B: Example 3

Using General Procedure II and ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoateas the appropriate 5-bromo-furo [2,3-d]pyrimidine derivative andPreparation 3b as the appropriate boronic acid derivative, Example 3 wasobtained as a mixture of diastereoisomers. HRMS calculated forC₃₆H₃₆ClFN₄O₆: 674.2307, found: 675.2367 and 675.2364 (M+H).

Example 4:(2R)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoic Acid Step A: Ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate

Using General procedure 1a and Preparation 2g as the appropriate lacticester derivative, ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoatewas obtained. MS: (M+H)⁺=595.0

Step B: Example 4

Using General Procedure II and ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoateas the appropriate 5-bromo-furo[2,3-d]pyrimidine derivative andPreparation 3b as the appropriate boronic acid derivative, Example 4 wasobtained as a mixture of diastereoisomers. HRMS calculated forC₄₀H₃₈ClFN₆O₆: 752.2525, found: 753.2645 and 753.2606 (M+H).

Example 5:(2R)-2-{[6-(5-chlorofuran-2-yl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}furo[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoic Acid Step A:2-[2-(2-furyl)-2-oxo-ethyl]propanedinitrile

46.2 mL IM NaOEt solution in EtOH (46.2 mmol) and 400 mL EtOH werecooled to 0° C. and 3.2 g malononitrile (48.4 mmol) was added. Themixture was stirred at 0° C. for 1 hour, then 8.35 g2-bromo-1-(2-furyl)ethanone (44 mmol) was added. The mixture was stirredat 0° C. for 1 hour, then at r.t. until no further conversion wasobserved. The volatiles were removed under reduced pressure, the residuewas digerated in Et₂O, filtered, then purified via flash chromatographyusing DCM and EtOAc as eluents to obtain2-[2-(2-furyl)-2-oxo-ethyl]propanedinitrile. MS: (M+H)+=175.2

Step B: 2-amino-5-(2-furyl)furan-3-carbonitrile

4.587 g 2-[2-(2-furyl)-2-oxo-ethyl]propanedinitrile (26.34 mmol) wasdissolved in 150 mL EtOH and 4.6 g Amberlite 15H⁺ was added. The mixturewas stirred at 90° C. until no further conversion was observed. Themixture was then filtered, washed with DCM and EtOAc. The filtrate wasconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain2-amino-5-(2-furyl)furan-3-carbonitrile. MS: (M+H)+=175.4

Step C: 6-(2-furyl)-3H-furo[2,3-d]pyrimidin-4-one

1310 mg 2-amino-5-(2-furyl)furan-3-carbonitrile (7.52 mmol) and 30 mLacetic formic anhydride were placed in a flask and stirred at r.t. for30 minutes. Then the volatiles were evaporated under reduced pressureand the residue was dissolved in 60 mL AcOH, and irradiated at 180° C.for 50 minutes. The mixture was cooled to r.t., and the crude productwas purified via flash chromatography using heptane and EtOAc as eluentsto obtain 6-(2-furyl)-3H-furo[2,3-d]pyrimidin-4-one. 1H NMR (400 MHz,DMSO-d₆): 12.68 (br s, 1H), 8.14 (s, 1H), 7.84 (m, 1H), 7.08 (s, 1H),6.94 (d, 1H), 6.67 (m, 1H)

Step D: 6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one

1.183 g 6-(2-furyl)-3H-furo[2,3-d]pyrimidin-4-one (5.85 mmol) wasdissolved in 55 mL THF and 860 mg NCS (6.44 mmol) was added. The mixturewas stirred at 40° C. until no further conversion was observed. Themixture was cooled to 0° C., and the precipitate was filtered, and driedto obtain 6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one. MS:(M+H)⁺=237.0

Step E: 5-bromo-6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one)

1000 mg 6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one (4.23 mmol)was dissolved in 40 mL AcOH, then 776 mg bromine (4.86 mmol) was added.The mixture was stirred at 40° C. until no further conversion wasobserved. Then the volatiles were removed under reduced pressure. Theresidue was digerated with DCM then filtered to obtain5-bromo-6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one. MS:(M−H)⁺=314.8

Step F: 5-bromo-4-chloro-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidine

1110 mg 5-bromo-6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one (3.52mmol) was dissolved in 8.21 mL POCl₃ (88.1 mmol) then 447 μL DMA (3.52mmol) was added. The mixture was stirred at 110° C. until no furtherconversion was observed. The mixture was then cooled to −78° C. and icewas added. It was sonicated then the precipitate was filtered. The crudeproduct was purified via flash chromatography using heptane and EtOAc aseluents to obtain5-bromo-4-chloro-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidine. MS:(M+H)⁺=335.0

Step G: Ethyl(2R)-2-[5-bromo-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate

1 eq. 5-bromo-4-chloro-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidine, 2 eq.Preparation 2g, 10 mL/mmol ^(t)BuOH and 5 eq. Cs₂CO₃ were placed in aflask and stirred at 55° C. until no further conversion was observed.The mixture was then concentrated under reduced pressure, diluted withbrine, neutralized with IM aqueous HCl solution, and extracted withEtOAc. The combined organic phases were dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via flash chromatography using heptane and EtOAc as eluentsto give ethyl(2R)-2-[5-bromo-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate.MS: (M+H)⁺=601.0

Step H: Example 5

Using General Procedure II and ethyl(2R)-2-[5-bromo-6-(5-chloro-2-furyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoateas the appropriate 5-bromo-furo[2,3-d]pyrimidine derivative andPreparation 3b as the appropriate boronic acid derivative, Example 5 wasobtained as a mixture of diastereoisomers. HRMS calculated forC₃₈H₃₆Cl₂N₆O₇: 758.2023, found: 759.2119 and 759.2156 (M+H).

Example 6:(2R)-3-{2-[(1-tert-butyl-1H-pyrazol-5-yl)methoxy]phenyl}-2-{[5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}propanoicAcid Step A: 1-tert-butyl-5-(dimethoxymethyl)-1H-pyrazole

1.2 eq. tert-butylhydrazine hydrochloride and 1 eq. Preparation 5a wasdissolved in dry methanol (0.5 mL/mmol), then 1.2 eq NaOEt was addedportionwise and the mixture was stirred at 75° C. for 2 hours. Thereaction mixture was cooled and concentrated under reduced pressure. Theresidue was diluted with water and it was extracted with DCM. Thecombined organic phases were dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The crude product was purifiedvia flash chromatography using heptane and EtOAc as eluents to give1-tert-butyl-5-(dimethoxymethyl)-1H-pyrazole. 1H NMR (400 MHz, DMSO-d₆)δ: 7.34 (d, 1H), 6.34 (d, 1H), 5.74 (s, 1H), 3.24 (s, 6H), 1.57 (s, 9H).We also obtained 1-tert-butyl-3-(dimethoxymethyl)-1H-pyrazole. 1H NMR(400 MHz, DMSO-d₆) δ: 7.75 (d, 1H), 6.18 (d, 1H), 5.34 (s, 1H), 3.24 (s,6H), 1.50 (s, 9H)

Step B: (1-tert-Butyl-1H-pyrazol-5-yl)methanol

1 eq. 1-tert-butyl-5-(dimethoxymethyl)-1H-pyrazole was stirred with IMaqueous HCl solution (3 mL/mmol) at 50° C. until no further conversionwas observed. The reaction mixture was cooled to 0° C., then 2.85 eq.solid NaOH was added portionwise. The pH was adjusted to 8 using 10%aqueous K₂CO₃ solution, then 2 eq. sodium borohydride was addedportionwise, keeping the temperature below 5° C. and stirred at 0° C.until no further conversion was observed. The mixture was extracted withEtOAc, the combined organic phases were dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via flash chromatography using heptane and EtOAc to obtain(1-tert-butyl-1H-pyrazol-5-yl)methanol. 1H NMR (400 MHz, DMSO-d₆) δ:7.27 (d, 1H), 6.19 (d, 1H), 5.31 (t, 1H), 4.61 (d, 2H), 1.56 (s, 9H)

Step C:(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoicAcid

2.51 g Preparation 2a (9.96 mmol), 2.0 g(1-tert-butyl-1H-pyrazol-5-yl)methanol (13 mmol) and 3.39 g triphenylphosphine (13 mmol) were dissolved in 12 mL dry toluene, then 5.9 mLDEAD (13 mmol) was added. The mixture was stirred at 50° C. undernitrogen atmosphere until no further conversion was observed. Thevolatiles were evaporated under reduced pressure. Then 30 mL Et₂O wasadded, the mixture was sonicated and filtered (to remove PPh₃ andPPh₃O). The filtrate was concentrated under reduced pressure. Theresidue was dissolved in THF, and then 2 g NaOH dissolved in 8 mL waterwas added. The mixture was stirred at 50° C. until no further conversionwas observed. Then it was acidified with 2M aqueous HCl solution, andTHF was removed under reduced pressure. The residue was extracted withDCM, dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure to obtain(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoicacid. MS (M+H): 319.0

Step D: Ethyl(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoate

7.2 g(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoicacid was dissolved in 75 mL EtOH, then 2 mL cc. H₂SO₄ was added. Themixture was stirred at 60° C. until no further conversion was observed.Then it was diluted with water, neutralized with saturated aqueousNaHCO₃ solution and extracted with dichloromethane. The combined organicphases were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure and purified via flashchromatography using EtOAc and MeOH as eluents to obtain ethyl(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoate.MS (M+H): 347.0

Step E: Ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]propanoate

Using General procedure 1a and ethyl(2R)-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoateas the appropriate lactic ester derivative, ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-tert-butyl-pyrazol-3-yl) methoxy]phenyl]propanoate wasobtained. MS (M+H): 636.6-638.6

Step F:2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-N,N-dimethyl-ethanamine

10.0 g Preparation 3a (37.2 mmol), 5.366 g N,N-dimethylethanolamine(60.3 mmol) and 15.8 g PPh₃ (60.3 mmol) were dissolved in 100 mL drytoluene and then 27 mL DEAD (60.3 mmol, 40% solution in toluene) wasadded dropwise. The mixture was stirred at 50° C. under argon atmosphereuntil no further conversion was observed. The volatiles were evaporatedunder reduced pressure and 100 mL Et₂O was added. The precipitated whitecrystals were filtered off and washed with Et₂O. The filtrate wasconcentrated under reduced pressure and purified via flashchromatography using CHCl₃ and MeOH as eluents. The resulting lightbrown oil was crystallized from hexane to give2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-N,N-dimethyl-ethanamine.

1H NMR (200 MHz, CDCl₃) δ: 7.63 (d, 1H), 6.75 (d, 1H), 4.15 (t, 2H),2.81 (t, 2H), 2.60 (s, 3H), 2.38 (s, 6H), 1.33 (s, 12H)

MS (M+H): 340.1

Step G: Example 6

Using General Procedure II and ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-tert-butylpyrazol-3-yl)methoxy]phenyl]propanoateas the appropriate 5-bromo-furo[2,3-d]pyrimidine derivative and2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-N,N-dimethyl-ethanamineas the appropriate boronic acid derivative, Example 6 was obtained. HRMScalculated for C₄₀H₄₁ClFN₅O₆: 741.2729, found: 742.2813 and 742.2808(M+H) for the two diastereomers.

Example 7:N-[(5S_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-2-methoxy-D-phenylalanineStep A:(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-methoxyphenyl)propanoicAcid

Using General Procedure Ib and (2R)-2-amino-3-(2-methoxyphenyl)propanoicacid as the appropriate amino acid derivative,(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-methoxyphenyl)propanoicacid was obtained. MS: (M+H)+=487.8

Step B: Example 7

1 eq.(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-methoxyphenyl)propanoic acid, 1.5 eq. Preparation 3b, 5 mol % AtaPhos and 2 eq.Cs₂CO₃ were stirred in a 1:1 mixture of THF and water (10 mL/mmol5-bromo-furo[2,3-d]pyrimidine derivative) and heated to 110° C. in a MWreactor until no further conversion was observed. Then the mixture wasdiluted with brine, the pH was set to 4 with IM aqueous HCl solution,and was extracted with DCM. The combined organic phases were dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The obtained mixture of diastereoisomers were purified andseparated via HILIC chromatography. Example 7 was obtained as the latereluting diastereoisomer. HRMS calculated for C₃₆H₃₇ClFN₅O₅: 673.2467,found: 337.6286 (M+2H).

Example 8:N-[(5S_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanineand Example 9:N-[(5R_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanineStep A:(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoicAcid

Using General Procedure Ib andD-(R)-2-amino-3-(2-hydroxy-phenyl)-propionic acid as the appropriateamino acid derivative,(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoicacid was obtained. MS: (M+H)⁺=473.6

Step B: Ethyl(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyl]propanoate

163 mg (2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoic acid was dissolved in 3 mL HClsolution (1.25M in EtOH) and stirred at 60° C. until no furtherconversion was observed. The mixture was concentrated under reducedpressure, diluted with water. The precipitate was filtered and purifiedvia flash chromatography using heptane and EtOAc as eluents to obtainethyl (2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl) propanoate. MS: (M+H)⁺=501.6

Step C: Ethyl(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyl]propanoate

500 mg ethyl(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoate (1 mmol), 540 mg Preparation 5b(2.5 mmol) and 656 mg PPh₃ (2.5 mmol) were dissolved in 20 mL drytoluene under N₂ atmosphere, then 576 mg DTAD (2.5 mmol) was added. Themixture was stirred at 60° C. until no further conversion was observed.The mixture was then concentrated under reduced pressure and purifiedvia flash chromatography using heptane and EtOAc as eluents to giveethyl (2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyl]propanoate. HRMS (M+H)+: 698.1402

Step D: Examples 8 and 9

1 eq. ethyl(2R)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyl]propanoate,1.5 eq. Preparation 3b, 5 mol % AtaPhos and 2 eq. Cs₂CO₃ were stirred ina 1:1 mixture of THF and water (10 mL/mmol 5-bromo-furo[2,3-d]pyrimidinederivative) and heated to 70° C. and stirred until no further conversionwas observed. Then the mixture was diluted with brine, the pH was set to4 with IM aqueous HCl solution, and was extracted with DCM. The combinedorganic phases were dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude intermediate was purifiedvia flash chromatography using DCM and MeOH as eluents. Then it wasdissolved in dioxane:water 1:1 (20 mL/mmol) and 10 eq. LiOH×H₂O wasadded. The mixture was stirred at r.t. until no further conversion wasobserved. Then it was diluted with brine, neutralized with 2M aqueousHCl solution, extracted with DCM. The combined organic phases were driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure to obtain a mixture of diastereoisomers. They were separatedand purified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents. Example 8 was obtained asthe earlier eluting diastereoisomer. HRMS calculated for C₄₇H₄₅ClFN₇O₆:857.3104, found: 429.6637 (M+2H). Example 9 was obtained as the latereluting diastereoisomer. HRMS calculated for C₄₇H₄₅ClFN₇O₆: 857.3104,found: 429.6648 (M+2H).

Example 10:N-[7-methyl-5-(naphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-d]pyrimidine

Into a 50 mL Schlenk tube under N₂ atmosphere 220 mg NaH (5.5 mmol) and40 mL dry THF were charged and the slurry was cooled to 0° C. Then 1471mg 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5 mmol) was added. After30 minutes stirring, 346 μL MeI (5.5 mmol) was added and the mixture wasallowed to warm up to r.t., and stirred until no further conversion wasobserved. The mixture was then diluted with saturated aqueous NH₄Clsolution, and extracted with DCM. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure to obtain4-chloro-5-iodo-7-methyl-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.65 (s, 1H), 7.98 (s, 1H), 3.83 (s, 3H)

MS: (M+H)⁺=294.0

Step B: 4-chloro-7-methyl-5-(1-naphthyl)pyrrolo[2,3-d]pyrimidine

1 eq. 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-d]pyrimidine, 1.1 eq.1-naphthaleneboronic acid neopentyl glycol ester, 1.1 eq. silvercarbonate, 0.15 eq. Pd(PPh₃)₄ and 2-Me-THF (15 mL/mmol5-iodo-pyrrolo[2,3-d]pyrimidine derivative) were stirred under N₂atmosphere at 110° C. until no further conversion was observed. Themixture was diluted with brine, neutralized with IM aqueous HClsolution, and extracted with DCM. The combined organic phases were driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and EtOAc as eluents to give4-chloro-7-methyl-5-(1-naphthyl)pyrrolo[2,3-d]pyrimidine. MS:(M+H)⁺=294.2

Step C: Example 10

Using General Procedure III and4-chloro-7-methyl-5-(1-naphthyl)pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative, Example 10 wasobtained. HRMS calculated for C₂₆H₂₂N₄O₂: 422.1743, found: 423.1804(M+H).

Example 11:N-[5-(naphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine

Into a 50 mL Schlenk tube under N₂ atmosphere 220 mg NaH (5.5 mmol) and40 mL dry THF were charged and the slurry was cooled to 0° C. Then 1471mg 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5 mmol) was added. After30 minutes stirring, 1.4 mL benzenesulfonyl chloride (5.25 mmol) wasadded and the mixture was allowed to warm up to r.t., and stirred untilno further conversion was observed. The mixture was then diluted withsaturated aqueous NH₄Cl solution, and extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure. Then it wasdigerated with MTBE, then filtered to obtain7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.75 (s, 1H), 8.22 (m, 2H), 7.95 (s, 1H),7.67 (m, 1H), 7.56 (m, 2H)

MS: (M+H)⁺=419.8

Step B:7-(benzenesulfonyl)-4-chloro-5-(1-naphthyl)pyrrolo[2,3-d]pyrimidine

1 eq. 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine, 1.1eq. 1-naphthaleneboronic acid neopentyl glycol ester, 1.1 eq. silvercarbonate, 0.15 eq.

Pd(PPh₃)₄ and 2-Me-THF (15 mL/mmol 5-iodo-pyrrolo[2,3-d]pyrimidinederivative) were stirred under N₂ atmosphere at 110° C. until no furtherconversion was observed. The mixture was diluted with brine, neutralizedwith IM aqueous HCl solution, and extracted with DCM. The combinedorganic phases were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viaflash chromatography using heptane and EtOAc as eluents to give7-(benzenesulfonyl)-4-chloro-5-(1-naphthyl)pyrrolo[2,3-d]pyrimidine.

1H NMR (400 MHz, CDCl₃) δ: 8.82 (s, 1H), 8.31 (m, 2H), 7.94 (m, 2H),7.84 (s, 1H), 7.71 (m, 1H), 7.60 (m, 2H), 7.56-7.48 (m, 3H), 7.48-7.38(m, 2H)

MS: (M+H)⁺=420.0

Step C: Example 11

Using General Procedure III and7-(benzenesulfonyl)-4-chloro-5-(1-naphthyl)pyrrolo [2,3-d]pyrimidine asthe appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative, Example 11 wasobtained. HRMS calculated for C₂₅H₂₀N₄O₂: 408.1586, found: 409.1670(M+H).

Example 12:N-[7-benzyl-6-ethyl-5-(naphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 1 and Example 13:N-[7-benzyl-6-ethyl-5-(naphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 2

Using General Procedure IVa and Preparation 6 as the appropriate5-bromo-pyrrolo [2,3-d]pyrimidine derivative and 1-naphthaleneboronicacid neopentyl glycol ester as the appropriate boronic acid derivative,Example 12 was obtained as the earlier eluting diastereoisomer. HRMScalculated for C₃₄H₃₀N₄O₂: 526.2369, found: 527.2431 (M+H). Example 13was obtained as the later eluting diastereoisomer. HRMS calculated forC₃₄H₃₀N₄O₂: 526.2369, found: 527.2423 (M+H).

Example 14:N-{6-ethyl-5-(naphthalen-1-yl)-7-[2-(naphthalen-1-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-D-phenylalanine,diastereoisomer 1 and Example 15:N-{6-ethyl-5-(naphthalen-1-yl)-7-[2-(naphthalen-1-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-D-phenylalanine,diastereoisomer 2 Step A:5-bromo-4-chloro-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidine

94 mg 2-(1-naphthyloxy)ethanol (0.5 mmol), 131 mg PPh₃ (0.5 mmol) and 66mg Preparation 1b (0.25 mmol) were dissolved in 2.5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 230 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.69 (s, 1H), 7.80 (dd, 2H), 7.51-7.31 (m,4H), 6.94 (d, 1H), 4.90 (t, 2H), 4.52 (t, 2H), 3.08 (q, 2H), 1.26 (t,3H)

MS: (M+H)⁺=430.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidine as the appropriate4-chloro-pyrrolo[2,3-d]pyrimidine derivative and D-phenylalanine as theappropriate amino acid derivative(2R)-2-[[5-bromo-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.96 (br s, 1H), 8.24 (s, 1H), 7.88 (d,1H), 7.82 (d, 1H), 7.52-7.32 (m, 4H), 7.29-7.15 (m, 5H), 6.94 (d, 1H),6.38 (d, 1H), 4.94 (q, 1H), 4.72 (t, 2H), 4.45 (t, 2H), 3.28 (m, 1H),3.18 (dd, 1H), 2.92 (q, 2H), 1.19 (t, 3H)

MS: (M+H)⁺=559.2

Step C: Examples 14 and 15

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-[2-(1-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as theappropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative and1-naphthaleneboronic acid neopentyl glycol ester as the appropriateboronic acid derivative, Example 14 was obtained as the earlier elutingdiastereoisomer. HRMS calculated for C₃₉H₃₄N₄O₃: 606.2631, found:607.2711 (M+H). Example 15 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₃₉H₃₄N₄O₃: 606.2631, found:607.2705 (M+H).

Example 16:N-[6-ethyl-5-(naphthalen-1-yl)-7-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 1 and Example 17:N-[6-ethyl-5-(naphthalen-1-yl)-7-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 2 Step A:5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidine

3.1 mL 2-phenylethanol (25.9 mmol), 3.397 g PPh₃ (12.95 mmol) and 3.40 gPreparation 1b (12.95 mmol) were dissolved in 110 mL dry THF under N₂atmosphere and cooled to 0° C. Then 11.87 mL DEAD (40% in toluene) wasadded dropwise. The mixture was stirred at 40° C. until no furtherconversion was observed. Then the volatiles were removed under reducedpressure and the residue was purified via flash chromatography usingheptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.61 (s, 1H), 7.32-7.16 (m, 3H), 7.11 (m,2H), 4.51 (t, 2H), 3.06 (t, 2H), 2.70 (q, 2H), 1.10 (t, 3H)

MS: (M+H)⁺=364.0

Step B:(2R)-2-[(5-bromo-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative(2R)-2-[(5-bromo-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid was obtained.

1H NMR (400 MHz, DMSO-d₆) δ: 12.80 (br s, 1H), 8.20 (s, 1H), 7.34-7.17(m, 8H), 7.13 (m, 2H), 6.45 (d, 1H), 4.91 (q, 1H), 4.33 (t, 2H), 3.31(dd, 1H), 3.18 (dd, 1H), 3.00 (t, 2H), 2.55 (q, 2H), 1.04 (t, 3H)

MS: (M+H)⁺=493.2

Step C: Examples 16 and 17

Using General Procedure IVa and(2R)-2-[(5-bromo-6-ethyl-7-phenethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative and1-naphthaleneboronic acid neopentyl glycol ester as the appropriateboronic acid derivative, Example 16 was obtained as the earlier elutingdiastereoisomer. HRMS calculated for C₃₅H₃₂N₄O₂: 540.2525, found:541.2592 (M+H). Example 17 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₃₅H₃₂N₄O₂: 540.2525, found:541.2619 (M+H).

Example 18:N-[6-ethyl-5-(naphthalen-1-yl)-7-(3-phenylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 1 and Example 19:N-[6-ethyl-5-(naphthalen-1-yl)-7-(3-phenylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine,diastereoisomer 2 Step A:5-bromo-4-chloro-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-d]pyrimidine

3.52 mL 3-phenyl-propanol (25.9 mmol), 3.397 g PPh₃ (12.95 mmol) and 3.4g Preparation 1b (12.95 mmol) were dissolved in 110 mL dry THF under N₂atmosphere and cooled to 0° C. Then 11.87 mL DEAD (40% in toluene) wasadded dropwise. The mixture was stirred at 40° C. until no furtherconversion was observed. Then the volatiles were removed under reducedpressure and the residue was purified via flash chromatography usingheptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.60 (s, 1H), 7.31-7.22 (m, 2H), 7.21-7.13(m, 3H), 4.32 (t, 2H), 2.85 (q, 2H), 2.65 (t, 2H), 2.05 (m, 2H), 1.16(t, 3H)

MS: (M+H)⁺=378.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-(3-phenylpropyl)pyrrolo [2,3-d]pyrimidine asthe appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative,(2R)-2-[[5-bromo-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid was obtained. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.95 (br s, 1H), 8.15(s, 1H), 7.33-7.12 (m, 10H), 6.35 (d, 1H), 4.94 (q, 1H), 4.16 (t, 2H),3.28 (dd, 1H), 3.16 (dd, 1H), 2.68 (q, 2H), 2.61 (t, 2H), 1.97 (m, 2H),1.09 (t, 3H)

MS: (M+H)⁺=507.2

Step C: Examples 18 and 19

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-(3-phenylpropyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate5-bromo-pyrrolo[2,3-d] pyrimidine derivative and 1-naphthaleneboronicacid neopentyl glycol ester as the appropriate boronic acid derivative,Example 18 was obtained as the earlier eluting diastereoisomer. HRMScalculated for C₃₆H₃₄N₄O₂: 554.2682, found: 555.2742 (M+H). Example 19was obtained as the later eluting diastereoisomer. HRMS calculated forC₃₆H₃₄N₄O₂: 554.2682, found: 555.2756 (M+H).

Example 20:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 21:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidine

65 mg Preparation 1b (0.25 mmol) was dissolved in 1 mL dry THF, then20.3 μL dry MeOH (0.5 mmol) and 0.5 mL cyanomethylenetributylphosphoranesolution (0.5 mmol, IM in toluene) was added. The mixture was stirred atr.t. until no further conversion was observed. The volatiles wereremoved under reduced pressure. The residue was purified via flashchromatography using heptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidine.

H NMR (400 MHz, CDCl₃) δ: 8.56 (s, 1H), 3.84, (s, 3H), 2.91 (q, 2H),1.26 (t, 3H)

MS: (M+H)⁺=274.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative,(2R)-2-[[5-bromo-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.05 (br s, 1H), 8.17 (s, 1H), 7.32-7.25(m, 2H), 7.25-7.18 (m, 3H), 6.32 (d, 1H), 4.97 (m, 1H), 3.68, (s, 3H),3.29 (dd, 1H), 3.18 (dd, 1H), 2.75 (q, 2H), 1.13 (t, 3H)

MS: (M+H)⁺=403.0

Step C: Examples 20 and 21

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 20was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₅H₂₅ClN₄O₂: 448.1666, found: 449.1753 (M+H). Example 21 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₂₅H₂₅ClN₄O₂:448.1666, found: 449.1752 (M+H).

Example 22:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-7-(cyclopropylmethyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 23:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-7-(cyclopropylmethyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A:5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidine

65 mg Preparation 1b (0.25 mmol) was dissolved in 1 mL dry THF, then 40μL cyclopropanemethanol (0.5 mmol) and 0.5 mLcyanomethylenetributylphosphorane solution (0.5 mmol, IM in toluene) wasadded. The mixture was stirred at r.t. until no further conversion wasobserved. The volatiles were removed under reduced pressure. The residuewas purified via flash chromatography using heptane and EtOAc as eluentsto obtain5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidine.

1H NMR (400 MHz, CDCl₃) δ: 8.54 (s, 1H), 4.18 (d, 2H), 2.94 (q, 2H),1.29 (t, 3H), 1.24-1.14 (m, 1H), 0.60-0.51 (m, 2H), 0.51-0.43 (m, 2H)

MS: (M+H)⁺=314.0

Step B:(2R)-2-[[5-bromo-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidineas the appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative,(2R)-2-[[5-bromo-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.05 (br s, 1H), 8.15 (s, 1H), 7.32-7.26(m, 2H), 7.26-7.20 (m, 3H), 6.34 (d, 1H), 4.94 (m, 1H), 4.05 (d, 2H)3.29 (dd, 1H), 3.18 (dd, 1H), 2.78 (q, 2H), 1.28-1.20 (m, 1H), 1.16 (t,3H), 0.47-0.42 (m, 2H), 0.42-0.37 (m, 2H)

MS: (M+H)⁺=443.0

Step C: Examples 22 and 23

Using General Procedure IVa and(2R)-2-[[5-bromo-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 22was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₈H₂₉ClN₄O₂: 488.1979, found: 489.2064 (M+H). Example 23 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₂₈H₂₉ClN₄O₂:488.1979, found: 489.2048 (M+H).

Example 24:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(prop-2-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 25:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(prop-2-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 7-allyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine

65 mg Preparation 1b (0.25 mmol) was dissolved in 1 mL dry THF, then 34μL allyl-alcohol (0.5 mmol) and 0.5 mL cyanomethylenetributylphosphoranesolution (0.5 mmol, IM in toluene) was added. The mixture was stirred atr.t. until no further conversion was observed. The volatiles wereremoved under reduced pressure. The residue was purified via flashchromatography using heptane and EtOAc as eluents to obtain7-allyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine.

1H NMR (400 MHz, CDCl₃) δ: 8.57 (s, 1H), 6.02-5.90 (m, 1H), 5.25-5.16(m, 1H), 5.00-4.85 (m, 3H), 2.87 (q, 2H), 1.26 (t, 3H)

MS: (M+H)⁺=300.0

Step B:(2R)-2-[[7-allyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and7-allyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative,(2R)-2-[[7-allyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.06 (br s, 1H), 8.16 (s, 1H), 7.34-7.26(m, 2H), 7.26-7.19 (m, 3H), 6.35 (d, 1H), 6.01-5.89 (m, 1H), 5.10 (dd,1H), 5.01-4.93 (m, 1H), 4.87-4.73 (m, 3H), 3.29 (dd, 1H), 3.18 (dd, 1H),2.70 (q, 2H), 1.12 (t, 3H)

MS: (M+H)⁺=429.0

Step C: Examples 24 and 25

Using General Procedure IVa and(2R)-2-[[7-allyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 24was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₇H₂₇ClN₄O₂: 474.1823, found: 475.1908. Example 25 was obtained as thelater eluting diastereoisomer. HRMS calculated for C₂₇H₂₇ClN₄O₂:474.1823, found: 475.1909.

Example 26:N-[7-(but-2-yn-1-yl)-(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 27:N-[7-(but-2-yn-1-yl)-(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 5-bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine

37 μL 2-butyn-1-ol (0.5 mmol), 131 mg PPh₃ (0.5 mmol) and 66 mgPreparation 1b (0.25 mmol) were dissolved in 2.5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 230 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo[2,3-d] pyrimidine.

1H NMR (400 MHz, CDCl₃) δ: 8.59 (s, 1H), 5.03 (q, 2H), 2.99 (q, 2H),1.77 (t, 3H), 1.33 (t, 3H)

MS: (M+H)⁺=312.0

Step B:(2R)-2-[(5-bromo-7-but-2-ynyl-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative(2R)-2-[(5-bromo-7-but-2-ynyl-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid was obtained.

¹H NMR (500 MHz, DMSO-d₆) δ: 13.25 (br s, 1H), 8.19 (s, 1H), 7.30-7.24(m, 2H), 7.24-7.16 (m, 3H), 6.45 (d, 1H), 5.02-4.96 (m, 2H), 4.93 (q,1H), 3.30 (dd, 1H), 3.19 (dd, 1H), 2.80 (q, 2H), 1.74 (t, 3H), 1.19 (t,3H)

MS: (M+H)⁺=441.0

Step C: Examples 26 and 27

Using General Procedure IVa and(2R)-2-[(5-bromo-7-but-2-ynyl-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 26was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₈H₂₇ClN₄O₂: 486.1823, found: 487.1893 (M+H). Example 27 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₂₈H₂₇ClN₄O₂:486.1823, found: 487.1893 (M+H).

Example 28:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 29:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A:5-bromo-4-chloro-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidine

72 μL trifluoroethanol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mgPreparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 460 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-(2,2,2-trifluoro ethyl)pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.62 (s, 1H), 4.90 (q, 2H), 2.94 (q, 2H),1.28 (t, 3H)

MS: (M+H)⁺=342.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-d]pyrimidinederivative and D-phenylalanine as the appropriate amino acid derivative(2R)-2-[[5-bromo-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.11 (br s, 1H), 8.23 (s, 1H), 7.33-7.26(m, 2H), 7.26-7.19 (m, 3H), 6.44 (d, 1H), 5.12 (q, 2H), 5.00-4.93 (m,1H), 3.30 (dd, 1H), 3.20 (dd, 1H), 2.78 (q, 2H), 1.14 (t, 3H)

MS: (M+H)⁺=471.0

Step C: Examples 28 and 29

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as theappropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative and Preparation3c as the appropriate boronic acid derivative, Example 28 was obtainedas the earlier eluting diastereoisomer. HRMS calculated forC₂₆H₂₄ClF₃N₄O₂: 516.1540, found: 517.1624 (M+H). Example 29 was obtainedas the later eluting diastereoisomer. HRMS calculated forC₂₆H₂₄ClF₃N₄O₂: 516.1540, found: 517.1606 (M+H).

Example 30:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-7-(2-cyclopentylethyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 31:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-7-(2-cyclopentylethyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A:5-bromo-4-chloro-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidine

124 μL 2-cyclopentylethanol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mgPreparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 460 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-4-chloro-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.55 (s, 1H), 4.31-4.20 (m, 2H), 2.89 (q,2H), 1.91-1.72 (m, 5H), 1.69-1.57 (m, 2H), 1.57-1.46 (m, 2H), 1.28 (t,3H), 1.23-1.05 (m, 2H)

MS: (M+H)⁺=356.0

Step B:(2R)-2-[[5-bromo-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidineas the appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative(2R)-2-[[5-bromo-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

¹H NMR (500 MHz, DMSO-d₆) δ: 13.04 (br s, 1H), 8.17 (s, 1H), 7.32-7.26(m, 2H), 7.25-7.19 (m, 3H), 6.32 (d, 1H), 5.00-4.92 (m, 1H), 4.17-4.09(m, 2H), 3.29 (dd, 1H), 3.18 (dd, 1H), 2.74 (q, 2H), 1.79-1.70 (m, 3H),1.70-1.62 (m, 2H), 1.60-1.50 (m, 2H), 1.50-1.42 (m, 2H), 1.15 (t, 3H),1.12-1.01 (m, 2H)

MS: (M+H)⁺=485.2

Step C: Examples 30 and 31

Using General Procedure IVa and(2R)-2-[[5-bromo-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 30was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₃₁H₃₅ClN₄O₂: 530.2449, found: 531.2528 (M+H). Example 31 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₃₁H₃₅ClN₄O₂:530.2449, found: 531.2547 (M+H).

Example 32:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(naphthalen-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 33:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(naphthalen-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A:5-bromo-4-chloro-6-ethyl-7-(1-naphthylmethyl)pyrrolo[2,3-d]pyrimidine

158 mg 1-naphthalenemethanol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mgPreparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 460 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-(1-naphthylmethyl)pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.58 (s, 1H), 8.09 (d, 1H), 7.95-7.89 (m,1H), 7.79 (d, 1H), 7.66-7.54 (m, 2H), 7.25 (t, 1H), 6.45 (dd, 1H), 6.03(s, 2H), 2.76 (q, 2H), 1.08 (t, 3H)

MS: (M+H)⁺=400.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-(1-naphthylmethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-(1-naphthylmethyl)pyrrolo [2,3-d]pyrimidineas the appropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative(2R)-2-[[5-bromo-6-ethyl-7-(1-naphthylmethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

¹H NMR (500 MHz, DMSO-d₆) δ: 13.14 (br s, 1H), 8.27 (d, 1H), 8.15 (s,1H), 7.98 (d, 1H), 7.83 (d, 1H), 7.66-7.56 (m, 2H), 7.37-7.20 (m, 6H),6.48 (d, 1H), 6.40 (d, 1H), 5.94 (s, 2H), 4.99 (q, 1H), 3.33 (dd, 1H),3.22 (dd, 1H), 2.62 (q, 2H), 0.89 (t, 3H)

MS: (M+H)⁺=529.0

Step C: Examples 32 and 33

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-(1-naphthylmethyl)pyrrolo[2,3-d]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid as the appropriate5-bromo-pyrrolo[2,3-d]pyrimidine derivative and Preparation 3c as theappropriate boronic acid derivative, Example 32 was obtained as theearlier eluting diastereoisomer. HRMS calculated for C₃₅H₃₁ClN₄O₂:574.2136, found: 575.2211 (M+H). Example 33 was obtained as the latereluting diastereoisomer. HRMS calculated for C₃₅H₃₁ClN₄O₂: 574.2136,found: 575.2203 (M+H).

Example 34:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 35:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A:5-bromo-4-chloro-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidine

138 mg 4-methoxybenzyl alcohol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mgPreparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂atmosphere and cooled to 0° C. Then 460 μL DEAD (0.5 mmol, 40% intoluene) was added dropwise. The mixture was stirred at 40° C. until nofurther conversion was observed. Then the volatiles were removed underreduced pressure and the residue was purified via flash chromatographyusing heptane and EtOAc as eluents to obtain5-bromo-4-chloro-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidine.MS: (M+H)⁺=380.0

Step B:(2R)-2-[[5-bromo-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidine as the appropriate4-chloro-pyrrolo[2,3-d]pyrimidine derivative and D-phenylalanine as theappropriate amino acid derivative,(2R)-2-[[5-bromo-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.07 (br s, 1H), 8.20 (s, 1H), 7.33-7.17(m, 5H), 7.03 (d, 2H), 6.85 (d, 2H), 6.37 (d, 1H), 5.37 (s, 2H), 4.99(q, 1H), 3.69 (s, 3H), 3.31 (dd, 1H), 3.20 (dd, 1H), 2.65 (q, 2H), 0.91(t, 3H)

MS: (M+H)⁺=508.8

Step C: Examples 34 and 35

Using General Procedure IVa and(2R)-2-[[5-bromo-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid asthe appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 34was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₃₂H₃₁ClN₄O₃: 554.2085, found: 555.2176 (M+H). Example 35 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₃₂H₃₁ClN₄O₃:554.2085, found: 555.2140 (M+H).

Example 36:N-[7-benzyl-(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 37:N-[7-benzyl-(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanine

Using General Procedure IVa and Preparation 6 as the appropriate5-bromo-pyrrolo [2,3-d]pyrimidine derivative and Preparation 3c as theappropriate boronic acid derivative, Example 36 was obtained as theearlier eluting diastereoisomer. HRMS calculated for C₃₁H₂₉ClN₄O₂:524.1979, found: 525.2048 (M+H). Example 37 was obtained as the latereluting diastereoisomer. HRMS calculated for C₃₁H₂₉ClN₄O₂: 524.1979,found: 525.2064 (M+H).

Example 38:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 39:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidine

76 μL 2-propanol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mg Preparation1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂ atmosphere andcooled to 0° C.

Then 460 μL DEAD (0.5 mmol, 40% in toluene) was added dropwise. Themixture was stirred at 40° C. until no further conversion was observed.Then the volatiles were removed under reduced pressure and the residuewas purified via flash chromatography using heptane and EtOAc as eluentsto obtain 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidine.

¹H NMR (400 MHz, CDCl₃) δ: 8.53 (s, 1H), 4.71 (sp, 1H), 2.92 (q, 2H),1.72 (d, 6H), 1.25 (t, 3H)

MS: (M+H)⁺=302.0

Step B:(2R)-2-[(5-bromo-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicAcid

Using General Procedure III and5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidine as theappropriate 4-chloro-pyrrolo[2,3-d]pyrimidine derivative andD-phenylalanine as the appropriate amino acid derivative(2R)-2-[(5-bromo-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid was obtained.

1H NMR (500 MHz, DMSO-d₆) δ: 13.04 (br s, 1H), 8.14 (s, 1H), 7.35-7.17(m, 5H), 6.33 (d, 1H), 4.95 (q, 1H), 4.64 (sp, 1H), 3.28 (dd, 1H), 3.17(dd, 1H), 2.76 (q, 2H), 1.59 (d, 6H), 1.11 (t, 3H)

MS: (M+H)⁺=431.2

Step C: Examples 38 and 39

Using General Procedure IVa and(2R)-2-[(5-bromo-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid as the appropriate 5-bromo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative, Example 38was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₇H₂₉ClN₄O₂: 476.1979, found: 477.2057 (M+H). Example 39 was obtainedas the later eluting diastereoisomer. HRMS calculated for C₂₇H₂₉ClN₄O₂:476.1979, found: 477.2063 (M+H).

Example 40:(2R)-2-[(7-benzyl-(5S_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]-3-phenylpropanoicAcid Step A: 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine

255 mg NaH (6.38 mmol) and 50 mL dry THF were charged into a 50 mLSchlenk tube under N₂ atmosphere and the slurry was cooled to 0° C. Then1.792 g Preparation 1b (5.8 mmol) was added. After stirring the mixturefor 30 minutes at 0° C., 773 μL benzyl bromide (6.38 mmol) was added andthe mixture was allowed to warm up to r.t., and stirred until no furtherconversion was observed. The mixture was then diluted with saturatedaqueous NH₄Cl solution, and extracted with DCM. The combined organiclayers were washed with brine, dried over MgSO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via flash chromatography using heptane and EtOAc as eluents toobtain 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine. 1HNMR (400 MHz, CDCl₃) δ: 8.58 (s, 1H), 7.35-7.20 (m, 3H), 7.10-6.96 (m,2H), 5.52 (s, 2H), 2.78 (q, 2H), 1.05 (t, 3H)

Step B: Methyl(2R)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate

1.639 g 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine (4.67mmol) was dissolved in 47 mL dry DMSO, then 2.948 g methyl(2R)-2-hydroxy-3-phenyl-propanoate (16.4 mmol) and 7.234 g Cs₂CO₃ (22.2mmol) were added and the mixture was stirred at 100° C. under N₂atmosphere until no further conversion was observed. Then it was dilutedwith water and brine, extracted with DCM. The organic layer was driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and ^(i)Pr₂O as eluents to obtain methyl(2R)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate.

¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s, 1H), 7.47 (d, 2H), 7.36-7.19 (m,6H), 7.06-6.96 (m, 2H), 5.60 (dd, 1H), 5.47 (s, 2H), 3.73 (s, 3H),3.41-3.28 (m, 2H), 2.72 (q, 2H), 1.03 (t, 3H)

MS: (M+H)⁺=494.2

Step C: Methyl(2R)-2-[7-benzyl-(5S_(a))-5-[3-chloro-2-methyl-4-hydroxyphenyl]-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoate

A mixture of 1.20 g methyl(2R)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate(2.43 mmol), 1.98 g Preparation 3a (7.21 mmol), 110 mg Pd(OAc)₂ (0.49mmol), 350 mg butyl-diadamantylphosphine (0.98 mmol), and 7.35 mL IMaqueous TBAOH in 18 mL DME was heated under MW irradiation at 100° C.until no further conversion was observed. The reaction mixture wasfiltered through Celite. Water was added to the filtrate, it wasacidified to pH=4 and extracted with MTBE. The combined organic phaseswere dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure.

The residue was heated in a mixture of 10 mL MeOH and 40 μL cc. H₂SO₄until no further conversion was observed. The volatiles were removedunder reduced pressure, the residue was diluted with water, the pH wasset to 5, and it was extracted with DCM. The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents to obtain methyl(2R)-2-[7-benzyl-(5S_(a))-5-[3-chloro-2-methyl-4-hydroxphenyl]-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoateas the later eluting diastereoisomer. 1H NMR (500 MHz, DMSO-d₆) δ: 10.14(s, 1H), 8.27 (s, 1H), 7.34-7.27 (m, 2H), 7.27-7.22 (m, 1H), 7.17-7.07(m, 4H), 7.05 (d, 2H), 6.98 (dd, 1H), 6.64 (d, 2H), 5.60 (d, 1H), 5.51(d, 1H), 5.43 (dd, 1H), 3.56 (s, 3H), 3.00 (dd, 1H), 2.85 (dd, 1H),2.60-2.51 (m, 1H), 2.48-2.38 (m, 1H), 2.04 (s, 3H), 0.84 (t, 3H)

Step D: Example 40

139 mg methyl(2R)-2-[7-benzyl-(5S_(a))-5-[3-chloro-2-methyl-4-hydroxyphenyl]-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl] oxy-3-phenyl-propanoate (0.25 mmol), 72 mg1-(2-hydroxyethyl)-4-methylpiperazine (0.50 mmol) and 166 mg resin boundPPh₃ (0.5 mmol) were dissolved in 3 mL dry toluene under N₂ atmosphere,then 115 mg DTAD (0.5 mmol) was added. The mixture was stirred at 50° C.until no further conversion was observed. The mixture was then dilutedwith DCM, filtered and the filtrate concentrated under reduced pressure,and purified via flash chromatography using heptane, EtOAc and MeOH aseluents. The obtained intermediate was dissolved in 10 mL MeOH, then 500mg LiOH×H₂O was added, and the mixture was stirred at 50° C. until nofurther conversion was observed. The mixture was diluted with brine,neutralized with IM aqueous HCl solution and extracted with DCM. Theorganic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viapreparative reversed phase chromatography using 40 mM aqueous NH₄OAcsolution (pH=4, adjusted with AcOH) and MeCN as eluents to obtainExample 40. HRMS calculated for C₃₈H₄₂ClN₅O₄: 667.2925, found: 668.2992(M+H).

Example 41:N-[6-bromo-7-(but-3-en-1-yl)-(5R_(a))-5-(3-chloro-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 42:N-[6-bromo-7-(but-3-en-1-yl)-(5S_(a))-5-(3-chloro-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine

5.0 g 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (17 mmol), 2.842 gK₂CO₃ (20.57 mmol), 2.15 mL 4-bromo-1-butene (20.57 mmol) and 26 mL dryDMF were stirred at r.t. under N₂ atmosphere until no further conversionwas observed. Then the mixture was poured into water and extracted withEtOAc. The combined organic layers were washed with water, dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and EtOAc to obtain7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine.

1H NMR (400 MHz, CDCl₃) δ: 8.62 (s, 1H), 7.38 (s, 1H), 5.82-5.69 (m,1H), 5.08 (s, 1H), 5.04 (dd, 1H), 4.33 (t, 2H), 2.60 (q, 2H)

MS: (M+H)⁺=334.0

Step B:(2R)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicAcid

Using General Procedure III and7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine as the appropriate4-chloro-pyrrolo[2,3-d]pyrimidine derivative and D-phenylalanine as theappropriate amino acid derivative,(2R)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid was obtained. 1H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.38 (s,1H), 7.35-7.28 (m, 3H), 7.28-7.22 (m, 2H), 7.02 (s, 1H), 6.28 (d, 1H),5.80-5.67 (m, 1H), 5.09-5.04 (m, 1H), 5.04-5.00 (s, 1H), 4.94-4.85 (m,1H), 4.22 (t, 2H), 3.51 (dd, 1H), 3.30 (dd, 1H), 2.54 (q, 2H)

Step C:(2R)-2-[[7-but-3-enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure IVb and(2R)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicacid as the appropriate 5-iodo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3c as the appropriate boronic acid derivative,(2R)-2-[[7-but-3-enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained. 1H NMR (500 MHz, DMSO-d₆)δ: 12.86 (br s, 1H), 8.24 (s, 1H), 7.55-7.43 (m, 1H), 7.33-6.95 (m, 6H),6.89-6.80 (m, 2H), 5.84-5.40 (m, 1H), 5.08-4.93 (m, 3H), 4.84 (br s,1H), 4.37-4.15 (m, 2H), 3.16 (d, 1H), 2.85 (dd, 1H), 2.56 (q, 2H),2.22-2.04 (s, 3H).

Step D: Examples 41 and 42

512 mg(2R)-2-[[7-but-3-enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid (1 mmol) was dissolved in 4.5 mL dry DMF and 187 mg NBS (1 mmol)was added. The mixture was stirred at r.t. until no further conversionwas observed. The mixture was then poured into water, extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 0.1% aqueous TFA solution and MeCN as eluents toobtain Example 41 as the earlier eluting diastereoisomer. HRMScalculated for C₂₆H₂₄BrClN₄O₂: 538.0771, found: 541.0831 (M+H). Example42 was obtained as the later eluting diastereoisomer. HRMS calculatedfor C₂₆H₂₄BrClN₄O₂: 538.0771, found: 541.0835 (M+H).

Example 43:N-[6-bromo-(5R_(a))-5-(3-chloro-2-methylphenyl)-7-(prop-2-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineand Example 44:N-[6-bromo-(5S_(a))-5-(3-chloro-2-methylphenyl)-7-(prop-2-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-D-phenylalanineStep A: 7-allyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine

176.5 mg 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (0.6 mmol), 100.7mg K₂CO₃ (0.73 mmol), 63 μL allyl bromide (0.73 mmol) and 1 mL dry DMFwere stirred at r.t. under N₂ atmosphere until no further conversion wasobserved. Then the mixture was poured into water and extracted withEtOAc. The combined organic layers were washed with water, dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and EtOAc to obtain7-allyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine. MS: (M+H)⁺=320.0

Step B:(2R)-2-[(7-allyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoicAcid

Using General Procedure III and7-allyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine as the appropriate4-chloro-pyrrolo[2,3-d]pyrimidine derivative and D-phenylalanine as theappropriate amino acid derivative,(2R)-2-[(7-allyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoic acid was obtained.

1H NMR (400 MHz, DMSO-d₆) δ: 13.09 (br s, 1H), 8.20 (s, 1H), 7.43 (s,1H), 7.34-7.18 (m, 5H), 6.52 (bd, 1H), 6.05-5.90 (m, 1H), 5.15 (dd, 1H),5.07-4.94 (m, 2H), 4.74 (d, 2H), 3.38 (dd, 1H), 3.15 (dd, 1H)

MS: (M+H)⁺=449.0

Step C:(2R)-2-[[7-allyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicAcid

Using General Procedure IVb and(2R)-2-[(7-allyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-phenyl-propanoic acid as the appropriate5-iodo-pyrrolo[2,3-d]pyrimidine derivative and Preparation 3c as theappropriate boronic acid derivative,(2R)-2-[[7-allyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

1H NMR (400 MHz, DMSO-d₆) δ: 12.89 (br s, 1H), 8.23 (s, 1H), 7.59-7.42(br, 1H), 7.31-7.10 (m, 6H), 6.91-6.81 (br, 2H), 6.12-5.98 (m, 1H), 5.16(dd, 1H), 5.09-4.96 (m, 2H), 4.90-4.76 (br, 3H), 3.17 (dd, 1H), 2.86(dd, 1H), 2.23-2.04 (br s, 3H)

MS: (M+H)⁺=447.0

Step D: Examples 43 and 44

447 mg(2R)-2-[[7-allyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoicacid (1 mmol) was dissolved in 4.5 mL dry DMF and 187 mg NBS (1 mmol)was added. The mixture was stirred at r.t. until no further conversionwas observed. The mixture was then poured into water, extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 0.1% aqueous TFA solution and MeCN as eluents toobtain Example 43 as the earlier eluting diastereoisomer. HRMScalculated for C₂₅H₂₂BrClN₄O₂: 524.0615, found: 525.0675 (M+H). Example44 was obtained as the later eluting diastereoisomer. HRMS calculatedfor C₂₅H₂₂BrClN₄O₂: 524.0615, found: 525.0674 (M+H).

Example 45:(2R)-2-[(7-benzyl-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]-3-phenylpropanoicAcid Step A: 7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine

1.68 g 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6 mmol), 1.24 mLbenzyl alcohol (12 mmol), 3.144 g PPh₃ (12 mmol) and 60 mL dry THF werecooled to 0° C. under N₂ atmosphere, then 5.5 mL DEAD solution (12 mmol,40% in toluene) was added and the mixture was stirred at 40° C. until nofurther conversion was observed. Then the mixture was poured into waterand extracted with Et₂O. The combined organic layers were washed withwater, dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc to obtain7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine.

¹H NMR (500 MHz, DMSO-d₆) δ: 8.67 (s, 1H), 8.12 (s, 1H), 7.32 (t, 2H),7.28 (t, 1H), 7.28 (d, 2H), 5.47 (s, 2H)

MS (M+H): 369.9

Step B: Methyl(2R)-2-(7-benzyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate

1 eq. 7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine, 3 eq. methyl(2R)-2-hydroxy-3-phenyl-propanoate, 3 eq. Cs₂CO₃ and dry DMSO (6mL/mmol) were stirred at 100° C. until no further conversion wasobserved. The mixture was acidified with IM aqueous HCl solution, andextracted with DCM. The organic layer was dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. The crudeproduct was purified via flash chromatography using heptane and EtOAc aseluents to give methyl(2R)-2-(7-benzyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate.MS (M+H): 514.1

Step C: Example 45

Using General Procedure IVb and methyl(2R)-2-(7-benzyl-5-iodo-pyrrolo[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoateas the appropriate 5-iodo-pyrrolo[2,3-d]pyrimidine derivative andPreparation 3b as the appropriate boronic acid derivative, methyl(2R)-2-[7-benzyl-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoate was obtained. It was dissolved in dioxane:water1:1 (20 mL/mmol) and 10 eq. LiOH×H₂O was added. The mixture was stirredat r.t. until no further conversion was observed. Then it was dilutedwith brine, neutralized with 2M aqueous HCl solution, extracted withDCM. The combined organic phases were dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via preparative reversed phase chromatography using 0.1%aqueous TFA solution and MeCN as eluents to obtain Example 45. HRMScalculated for C₃₆H₃₈ClN₅O₄: 639.2612, found: 640.2654 (M+H).

Example 46:N-[5-(3-chloro-2-methylphenyl)-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizin-4-yl]-D-phenylalanine

210 mg 1:1 mixture of Examples 43 and 44 (mixture of the twodiastereoisomers, 0.4 mmol) was dissolved in 3 mL MeOH and 70 μL cc.H₂SO₄ (1.2 mmol) was added. The mixture was stirred at r.t. until nofurther conversion was observed. The mixture was poured into icy water,neutralized with saturated aqueous NaHCO₃ solution and extracted withEtOAc. The combined organic phases were washed with brine, dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. Then it was dissolved in dry THF (6 mL/mmol), and was cooledto 0° C. 5 eq. 9-borabicyclo[3.3.1]nonane solution (0.5M in THF) wasadded and the mixture was stirred at r.t. until no further conversionwas observed. Then 20 eq. 2M aqueous NaOH solution and 20 mol %PdCl₂×dppf was added. The mixture was stirred at 80° C. until no furtherconversion was observed. Then it was filtered through Celite, washedwith EtOAc. The layers of the filtrate were separated, the aqueous layerwas acidified to pH 3 with 2M aqueous HCl solution, then extracted withEtOAc. The combined organic phases were dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via preparative reversed phase chromatography using 40 mMaqueous NH₄OAc solution (pH=4, adjusted with AcOH) and MeCN as eluentsto obtain Example 46 as a mixture of diastereoisomers. HRMS calculatedfor C₂₅H₂₃ClN₄O₂: 446.1510, found: 447.159 and 447.1591 (M+H).

Example 47:N-[(5R_(a))-5-(3-chloro-2-methylphenyl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-4-yl]-D-phenylalanineand Example 48:N-[(5S_(a))-5-(3-chloro-2-methylphenyl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-4-yl]-D-phenylalanine

1.29 g 1:1 mixture of Examples 41 and 42 (mixture of the twodiastereoisomers, 2.3 mmol) was dissolved in 10 mL MeOH and 0.4 mL cc.H₂SO₄ (6.9 mmol) was added.

The mixture was stirred at r.t. until no further conversion wasobserved. The mixture was poured into icy water, neutralized withsaturated aqueous NaHCO₃ solution and extracted with EtOAc. The combinedorganic phases were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure. Then it wasdissolved in dry THF (6 mL/mmol), and was cooled to 0° C. 5 eq.9-borabicyclo[3.3.1]nonane solution (0.5M in THF) was added and themixture was stirred at r.t. until no further conversion was observed.Then 20 eq. 2M aqueous NaOH solution and 20 mol % PdCl₂×dppf was added.The mixture was stirred at 80° C. until no further conversion wasobserved. Then it was filtered through Celite, washed with EtOAc. Thelayers of the filtrate were separated, the aqueous layer was acidifiedto pH 3 with 2M aqueous HCl solution, then extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via preparative reversed phase chromatography using 0.1%aqueous TFA solution and MeCN as eluents. Example 47 was obtained as theearlier eluting diastereoisomer. HRMS calculated for C₂₆H₂₅ClN₄O₂:460.1666, found: 461.1747 (M+H). Example 48 was obtained as the latereluting diastereoisomer. HRMS calculated for C₂₆H₂₅ClN₄O₂: 460.1666,found: 461.1752 (M+H).

Example 49:(2R)-2-{[(3S_(a))-3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-1-benzothiophen-4-yl]oxy}-3-phenylpropanoicAcid and Example 50:(2R)-2-{[(3R_(a))-3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-1-benzothiophen-4-yl]oxy}-3-phenylpropanoicAcid Step A: (2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoicAcid

270 mg (2R)-2-hydroxy-3-phenyl-propanoic acid (1.63 mmol), 40 mg CuI(0.21 mmol) and 325 mg Cs₂CO₃ (1 mmol) were measured into a 7 mL vialequipped with screw cap and rubber septum. The vial was purged withargon and 5 mL dry DMF and 288 mg 2-ethyl-4-iodo-benzo[b]thiophene (1mmol) were added by syringe. The mixture was stirred at 110° C. in darkfor 20 hours. All further steps were carried out in dark or at redlight. 10 mL water was added and the pH was set to 3 with 2M aqueous HClsolution. Then it was extracted with EtOAc. The combined organic layerwas dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified on a preparative TLCplate (silica layer, toluene:AcOH 9:1 eluent) to obtain(2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoic acid. 1H NMR(500 MHz, DMSO-d₆) δ: 12.53 (br s, 1H), 7.42-7.36 (m, 3H), 7.30 (t, 2H),7.25-7.18 (m, 1H), 7.13 (t, 1H), 7.07 (br, 1H), 6.65 (d, 1H), 4.98 (dd,1H), 3.29 (dd, 1H), 3.22 (dd, 1H), 2.89 (q, 2H), 1.30 (t, 3H)

Step B: Methyl (2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate

1.434 g (2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoic acid(4.39 mmol) was dissolved in 20 mL MeOH and 20 μL cc. H₂SO₄ was added.The mixture was stirred at 80° C. until no further conversion wasobserved. The mixture was concentrated under reduced pressure, thendiluted with water, neutralized with saturated aqueous NaHCO₃ solutionand extracted with DCM. The combined organic phases were washed withbrine, dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure to obtain methyl(2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate. 1H NMR (400MHz, CDCl₃) δ: 7.46-7.33 (m, 5H), 7.33-7.26 (m, 1H), 7.16 (bd, 1H), 7.13(t, 1H), 6.65 (d, 1H), 4.99 (dd, 1H), 3.75 (s, 3H), 3.46-3.32 (m, 2H),3.01-2.91 (m, 2H), 1.42 (t, 3H)

Step C: Methyl(2R)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3-phenyl-propanoate

1.278 g methyl-(2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate(3.75 mmol), 2.284 g I₂ (9 mmol), and 2.5 g Ag₂SO₄ (8 mmol) weredissolved in 10 mL EtOH and stirred at r.t. until no further conversionwas observed. The mixture was then filtered, the filtrate wasconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain 860 mgmethyl(2R)-2-(2-ethyl-3,7-diiodo-benzothiophen-4-yl)oxy-3-phenyl-propanoatethat was dissolved in 20 mL THF, 150 mg 10% Pd/C was added and themixture was stirred at r.t. under 4 bar H₂ atmosphere until no furtherconversion was observed. Then it was filtered through Celite, thefiltrate was concentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain methyl(2R)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3-phenyl-propanoate. 1HNMR (500 MHz, DMSO-d₆) δ: 7.53 (d, 1H), 7.49-7.41 (m, 2H), 7.34-7.27 (m,2H), 7.26-7.18 (m, 2H), 6.77 (d, 1H), 5.33 (dd, 1H), 3.61 (s, 3H), 3.43(dd, 1H), 3.32 (dd, 1H), 2.94-2.85 (m, 2H), 1.25 (t, 3H)

Step D: Examples 49 and 50

320 mg methyl(2R)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3-phenyl-propanoate (0.686mmol) and 368 mg Preparation 3a (1.37 mmol) were dissolved in 4 mL2-Me-THF under N₂ atmosphere, then 1.37 mL TBAOH solution (1.37 mmol, IMin THF) and 49 mg AtaPhos (0.069 mmol) were added and the mixture wasstirred at 90° C. in a closed vial until no further conversion wasobserved. Then it was diluted with 30 mL DCM, washed with 10 mL IMaqueous HCl solution. The organic layer was concentrated under reducedpressure, then dissolved in 5 mL MeOH. 100 mg LiOH×H₂O was added, andthe mixture was stirred at 50° C. until no further conversion wasobserved. Then it was diluted with brine, neutralized with IM aqueousHCl solution and extracted with DCM. The organic layer was dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 0.1% aqueous TFA solution and MeCN as eluents.Example 49 was obtained as the later eluting diastereoisomer. HRMScalculated for C₂₆H₂₃ClO₄S: 466.1006, found: 465.0956 (M−H). Example 50was obtained as the earlier eluting diastereoisomer. HRMS calculated forC₂₆H₂₃ClO₄S: 466.1006, found: 465.0971 (M−H).

Example 51:(2R)-2-[((3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-ethyl-1-benzothiophen-4-yl)oxy]-3-phenylpropanoicAcid Step A: Methyl(2R)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4-yl]oxy-3-phenyl-propanoate

140 mg Example 49 (0.3 mmol) was dissolved in 3 mL MeOH and 50 μL cc.H₂SO₄ was added. The mixture was stirred at 80° C. until no furtherconversion was observed. The mixture was concentrated under reducedpressure and the residue was diluted with water, neutralized withsaturated aqueous NaHCO₃ solution and extracted with DCM. The combinedorganic phases were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via flash chromatography using heptane and EtOAc as eluentsto obtain methyl(2R)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4-yl]oxy-3-phenyl-propanoate.

1H NMR (500 MHz, DMSO-d₆) δ: 10.02 (s, 1H), 7.49 (d, 1H), 7.23-7.12 (m,4H), 7.02 (d, 1H), 6.92 (d, 1H), 6.89-6.86 (m, 2H), 6.62 (d, 1H), 5.01(dd, 1H), 3.50 (s, 3H), 2.72 (dd, 1H), 2.60-2.51 (m, 2H), 2.38 (dd, 1H),1.96 (s, 3H), 1.12 (t, 3H)

Step B: Example 51

63 mg methyl(2R)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4-yl]oxy-3-phenyl-propanoate(0.13 mmol), 23 mg 1-(2-hydroxyethyl)-4-methylpiperazine (0.156 mmol)and 41 mg PPh₃ (0.156 mmol) were dissolved in 2 mL dry THF under N₂atmosphere, then 36 mg DTAD (0.156 mmol) was added. The mixture wasstirred at 50° C. until no further conversion was observed. The mixturewas then concentrated under reduced pressure, and purified via flashchromatography using heptane, EtOAc and MeOH as eluents. The obtainedintermediate was dissolved in 5 mL MeOH, then 100 mg LiOH×H₂O was added,and the mixture was stirred at 50° C. until no further conversion wasobserved. Then it was diluted with brine, neutralized with 1 M aqueousHCl solution and extracted with DCM. The organic layer was dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 40 mM aqueous NH₄OAc solution (pH=4, adjusted withAcOH) and MeCN as eluents to obtain Example 51. HRMS calculated forC₃₃H₃₇ClN₂O₄S: 592.2163, found: 593.2238 (M+H).

Example 52:(2R)-2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzothiophen-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid and Example 53:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzothiophen-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A: (3-bromophenyl)N,N-diethylcarbamate

5.0 g 3-bromophenol (28.9 mmol) and 4.31 g diethylcarbamoyl chloride(31.8 mmol) were dissolved in 50 mL pyridine and stirred at 100° C.until no further conversion was observed. Then the mixture wasconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain(3-bromophenyl) N,N-diethylcarbamate. MS (EI, 70 eV) m/z (% relativeintensity, [ion]): 56 (9), 72 (42), 100 (100), 174 (4), 176 (4), 271 (4,[M⁺]), 273 (4, [M⁺])

Step B: (3-bromo-2-iodo-phenyl) N,N-diethylcarbamate

2.72 g (3-bromophenyl) N,N-diethylcarbamate (10 mmol) was dissolved in50 mL dry THF under N₂ atmosphere and cooled to −78° C. 6 mL LDAsolution (12 mmol, 2M in THF, heptane, ethyl benzene) was added and themixture was stirred at −78° C. for 30 minutes. Then 3.18 g I₂ (12.5mmol) was added and the mixture was stirred at −78° C. for 30 minutesthen it was allowed to warm up to r.t. Then the mixture was concentratedunder reduced pressure and purified via flash chromatography usingheptane and EtOAc as eluents to obtain (3-bromo-2-iodo-phenyl)N,N-diethylcarbamate. 1H NMR (400 MHz, DMSO-d₆) δ: 7.60 (dd, 1H), 7.35(t, 1H), 7.17 (dd, 1H), 3.47 (q, 2H), 3.31 (q, 2H), 1.27 (t, 3H), 1.14(t, 3H)

Step C: [3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl]N,N-diethylcarbamate

2.60 g (3-bromo-2-iodo-phenyl) N,N-diethylcarbamate (6.53 mmol), 863 mg1-ethynyl-4-fluorobenzene (7.19 mmol), 229 mg Pd(PPh₃)₂Cl₂ (0.33 mmol),130 mg copper(I) iodide (0.65 mmol) and 1.43 g diethylamine (19.6 mmol)were dissolved in 25 mL dry DMF and stirred at 50° C. until no furtherconversion was observed. The mixture was diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents to obtain[3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl] N,N-diethylcarbamate. MS(EI, 70 eV) m/z (% relative intensity, [ion]): 56 (2), 72 (35), 100(100), 261 (2), 263 (2), 389 (2, [M⁺]), 391 (2, [M⁺])

Step D: [2-[2-(4-fluorophenyl)ethynyl]-3-methylsulfanyl-phenyl]N,N-diethylcarbamate

2.5 g [3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl] N,N-diethylcarbamate(6.56 mmol) was dissolved in 65 mL dry THF and cooled to −78° C., then4.3 mL ^(n)BuLi solution (6.88 mmol, 1.6M in hexanes) was added. Themixture was stirred at −78° C. for 30 minutes. Then 742 mg S₂Me₂ (7.87mmol) was added and the mixture was stirred at −78° C. for 30 minutes,then it was allowed to warm up to r.t. The mixture was then concentratedunder reduced pressure and purified via flash chromatography usingheptane and EtOAc as eluents to obtain[2-[2-(4-fluorophenyl)ethynyl]-3-methylsulfanyl-phenyl]N,N-diethylcarbamate.MS (EI, 70 eV) m/z (% relative intensity, [ion]): 56 (2), 72 (46), 100(100), 342 (40), 357 (1, [M⁺])

Step E: [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-yl]N,N-diethylcarbamate

1100 mg 2-[2-(4-fluorophenyl)ethynyl]-3-methylsulfanyl-phenyl]N,N-diethylcarbamate (3.08 mmol) and 937 mg I₂ (3.7 mmol) were dissolvedin 20 mL DCM and stirred at r.t. until no further conversion wasobserved. The mixture was then diluted with 10% aqueous Na₂SO₃ solutionand extracted with DCM. The combined organic layers were washed withbrine, to give [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-yl]N,N-diethylcarbamate. ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (dd, 1H), 7.56 (m,2H), 7.40 (t, 1H), 7.18 (m, 2H), 7.12 (dd, 1H), 3.60 (q, 2H), 3.46 (q,2H), 1.36 (t, 3H), 1.26 (t, 3H) MS (EI, 70 eV) m/z (% relativeintensity, [ion]): 72 (42), 100 (100), 170 (16), 342 (37), 369 (5), 469(1, [M⁺])

Step F:[3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-yl] N,N-diethylcarbamate

1 eq. [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-yl]N,N-diethylcarbamate, 2 eq. Preparation 3b, 2 eq. Cs₂CO₃, 0.1 eq.Ataphos and THF:water 3:1 (10 mL/mmol benzothiophene derivative) werestirred under N₂ atmosphere at 70° C. until no further conversion wasobserved. The mixture was diluted with water and extracted with DCM.

The organic phase was dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viaflash chromatography using heptane and EtOAc as eluents to give[3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-yl]N,N-diethylcarbamate. MS: (M+H)⁺=610.2

Step G:3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-ol

1.8 g[3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-yl] N,N-diethylcarbamate (3 mmol) was dissolvedin 80 mL EtOH and 1.2 g NaOH (30 mmol) was added. The mixture wasstirred at 80° C. until no further conversion was observed. The mixturewas concentrated under reduced pressure and purified via flashchromatography using DCM and MeOH as eluents to obtain3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-ol.MS: (M+H)⁺=511.2

Step H: Examples 52 and 53

470 mg3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-ol (0.92 mmol), 1.12 g Preparation 2d (2.76 mmol)and 726 mg PPh₃ (2.76 mmol) were dissolved in 10 mL dry toluene, then635 mg DTAD (2.76 mmol) was added. The mixture was stirred at 50° C.until no further conversion was observed. The mixture was thenconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents. The formedintermediate was dissolved in 10 mL dioxane:water 1:1, 400 mg LiOH×H₂Owas added, and the mixture was stirred at r.t. until no furtherconversion was observed. It was neutralized with 2M aqueous HCl solutionand extracted with DCM. The combined organic phases were dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.Example 52 was obtained as the earlier eluting diastereoisomer. HRMScalculated for C₄₉H₄₆ClFN₄O₆S: 872.2811, found: 437.1457 (M+2H). Example53 was obtained as the later eluting diastereoisomer. HRMS calculatedfor C₄₉H₄₆ClFN₄O₆S: 872.2811, found: 437.1491 (M+2H).

Example 54:2-benzyl-3-[3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-1-benzothiophen-4-yl]propanoicAcid Step A: Methyl(Z)-2-benzyl-3-(2-ethylbenzothiophen-4-yl)prop-2-enoate

576 mg 2-ethyl-4-iodo-benzo[b]thiophene (2 mmol), 717 mg methyl2-benzylacrylate (4 mmol), 556 μL TEA (4 mmol) and 24 mg PdCl₂ (0.1mmol) were dissolved in 10 mL DMF and stirred at 130° C. in a MW reactoruntil no further conversion was observed. The mixture was concentratedunder reduced pressure and purified via flash chromatography usingheptane and EtOAc as eluents to obtain methyl(Z)-2-benzyl-3-(2-ethylbenzothiophen-4-yl)prop-2-enoate. 1H NMR (400MHz, CDCl₃) ratio of diastereoisomers 1.00/0.77=major/minor, δ:8.06-8.28 (s, 1H), 7.68-7.76 (d, 1H), 7.44-6.98 (m, 8H), 4.25-3.93 (s,2H), 3.78-3.82 (s, 3H), 2.97-2.99 (q, 2H), 1.41-1.43 (t, 3H)

Step B: Methyl 2-benzyl-3-(2-ethylbenzothiophen-4-yl)propanoate

432 mg methyl (Z)-2-benzyl-3-(2-ethylbenzothiophen-4-yl)prop-2-enoate(1.28 mmol), 137 mg 10% Pd/C, 5 mL AcOH and 20 mL MeOH were stirredunder 4 bar H₂ atmosphere at r.t. until no further conversion wasobserved. The mixture was filtered through Celite, the filtrate wasconcentrated under reduced pressure and purified via flashchromatography using heptane and EtOAc as eluents to obtain methyl2-benzyl-3-(2-ethylbenzothiophen-4-yl)propanoate. 1H NMR (400 MHz,CDCl₃) δ: 7.61 (d, 1H), 7.38-7.05 (m, 7H), 6.80 (s, 1H), 3.50 (s, 3H),3.28-3.18 (m, 1H), 3.11-3.00 (m, 3H), 2.90 (q, 2H), 2.86-2.77 (m, 1H),1.35 (t, 3H)

Step C: Methyl 2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4-yl)propanoate

346 mg methyl 2-benzyl-3-(2-ethylbenzothiophen-4-yl)propanoate (1.02mmol), 305 mg 1₂ (1.2 mmol) and 468 mg Ag₂SO₄ (1.5 mmol) were dissolvedin 5 mL EtOH and stirred at r.t. until no further conversion wasobserved. The mixture was filtered, the filtrate was concentrated underreduced pressure and purified via flash chromatography using heptane andEtOAc as eluents to obtain methyl2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4-yl)propanoate. 1H NMR (400MHz, CDCl₃) δ: 7.67 (dd, 1H), 7.28-7.06 (m, 7H), 4.29-4.17 (m, 1H),3.80-3.71 (m, 1H), 3.32 (s, 3H), 3.28-3.21 (m, 1H), 3.08-3.00 (m, 2H),2.97 (q, 2H), 1.35 (t, 3H)

Step D: Example 54

1 eq. methyl 2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4-yl)propanoate, 2eq. Preparation 3a, 2 eq. TBAOH solution (IM in water), 0.1 eq. Ataphosand 2-Me-THF (5 mL/mmol benzothiophene derivative) were stirred under N₂atmosphere at 100° C. until no further conversion was observed. Themixture was diluted with water and extracted with DCM. The organic layerwas dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The formed intermediate was dissolved in MeOH (5mL/mmol benzothiophene derivative), 10 eq. LiOH×H₂O was added, and themixture was stirred at r.t. until no further conversion was observed. Itwas neutralized with 2M aqueous HCl solution and extracted with DCM. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified using preparative reversed phase chromatography using 0.1%aqueous TFA solution and MeCN as eluents to give Example 54. HRMScalculated for C₂₇H₂₅ClO₃S: 464.1213, found: 463.1158 (M−H).

Example 55:(2R)-2-{[(1R_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid and Example 56:(2R)-2-{[(1S_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid

600 mg Preparation 7b (0.86 mmol) was dissolved in 20 mL dioxane:water1:1 and 600 mg LiOH×H₂O was added. The mixture was stirred at r.t. untilno further conversion was observed. Then it was diluted with water,acidified with IM aqueous HCl solution and extracted with DCM. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure and purified viapreparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃solution and MeCN as eluents. Example 55 was obtained as the earliereluting diastereoisomer. HRMS calculated for C₃₈H₃₉ClFN₃O₅: 671.2562,found: 672.2618 (M+H). Example 56 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₃₈H₃₉ClFN₃O₅: 671.2562, found:672.2652 (M+H).

Example 57:(2R)-2-{[3-chloro-(1S_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid

240 mg Preparation 7b (0.34 mmol) was dissolved in 3 mL DCM and 46 mgNCS (0.34 mmol) was added. The mixture was stirred at r.t. until nofurther conversion was observed. Then it was diluted with water andextracted with DCM. The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thenit was dissolved in 5 mL dioxane:water 1:1 and 140 mg LiOH×H₂O wasadded. The mixture was stirred at r.t. until no further conversion wasobserved. Then it was diluted with water, acidified with IM aqueous HClsolution and extracted with DCM. The combined organic phases were driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via preparative reversed phasechromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.Example 57 was obtained as the later eluting diastereoisomer. HRMScalculated for C₃₈H₃₈Cl₂FN₃O₅: 705.2173, found: 706.2227 (M+H).

Example 58:(2R)-2-{[(1R_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(furan-2-yl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid and Example 59:(2R)-2-{[(1S_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(furan-2-yl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid and Example 60:(2R)-2-{[(1S_(a))-1-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(5-fluorofuran-2-yl)-1H-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid Step A:4-[7-benzyloxy-2-(5-fluoro-2-furyl)indol-1-yl]-2-chloro-3-methyl-phenol

1360 mg Preparation 7a (2 mmol), 848 mg2-(5-fluoro-2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4 mmol),2123 mg K₃PO₄ (10 mmol), 45 mg Pd(OAc)₂ (0.2 mmol) and 164 mg SPhos (0.4mmol) were dissolved in 30 mL dry toluene and stirred at 75° C. until nofurther conversion was observed. The solvent was then removed underreduced pressure, the residue was purified via flash chromatographyusing heptane and EtOAc as eluents. Then 2 mL TBAF solution (2 mmol, IMin THF) and 25 mL THF were added and the mixture was stirred at r.t.until no further conversion was observed. Then the mixture wasconcentrated under reduced pressure, and the residue was purified viaflash chromatography using heptane and EtOAc as eluents to give4-[7-benzyloxy-2-(5-fluoro-2-furyl)indol-1-yl]-2-chloro-3-methyl-phenol.MS: (M+H)⁺=448.0

Step B:7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indole

650 mg4-[7-benzyloxy-2-(5-fluoro-2-furyl)indol-1-yl]-2-chloro-3-methyl-phenol(1.01 mmol), 288 mg 1-(2-hydroxyethyl)-4-methylpiperazine (2 mmol) and786 mg PPh₃ (3 mmol) were dissolved in 20 mL dry toluene. Then 690 mgDTAD (3 mmol) was added and the mixture was stirred at 45° C. until nofurther conversion was observed. Then it was concentrated under reducedpressure, and was purified via flash chromatography using DCM and MeOHas eluents to give 7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indole. MS:(M+H)⁺=574.2

Step C: The mixture of1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(2-furyl)indol-7-oland1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indol-7-ol

1300 mg7-benzyloxy-1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indole(2.26 mmol) was dissolved in 100 mL MeOH and 100 mg 10% Pd/C was added.The mixture was stirred under 1 bar H₂ atmosphere at r.t. overnight. Themixture was filtered through Celite and the filtrate was concentratedunder reduced pressure to give a 7:3 mixture of1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(2-furyl)indol-7-ol(MS: (M+H)⁺=466.2) and1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indol-7-ol(MS: (M+H)⁺=484.2).

Step D: Examples 58, 59 and 60

465 mg of the 7:3 mixture of1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(2-furyl)indol-7-oland1-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indol-7-ol(1 mmol), 449 mg ethyl (2S)-2-hydroxy-3-phenyl-propanoate (2 mmol) and786 mg PPh₃ (3 mmol) were dissolved in 10 mL dry toluene. Then 691 mgDTAD (3 mmol) was added and the mixture was stirred at 45° C. until nofurther conversion was observed. Then it was concentrated under reducedpressure, and the residue was purified via flash chromatography usingDCM and MeOH as eluents. Then it was dissolved in 5 mL dioxane:water 1:1and 140 mg LiOH×H₂O was added. The mixture was stirred at r.t. until nofurther conversion was observed. Then it was diluted with water,acidified with IM aqueous HCl solution and extracted with DCM. Thecombined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents. Example 58 was obtained asthe earlier eluting diastereoisomer. HRMS calculated for C₃₆H₃₈ClN₃O₆:643.2449, found: 644.2512 (M+H). Example 59 was obtained as the latereluting diastereoisomer. HRMS calculated for C₃₆H₃₈ClN₃O₆: 643.2449,found: 644.2521 (M+H). Example 60 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₃₆H₃₇ClFN₃O₆: 661.2355, found:662.2411 (M+H).

Example 61:(2R)-2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid and Example 62:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-methoxyphenyl)propanoicAcid Step A: Ethyl(2S)-3-(2-methoxyphenyl)-2-(p-tolylsulfonyloxy)propanoate

3000 mg Preparation 2f (13.38 mmol) was dissolved in 10 mL pyridine and2933 mg TsCl (15.38 mmol) was added at 0° C. The mixture was stirred atr.t. until no further conversion was observed. Then the mixture wasdiluted with water and extracted with EtOAc. The combined organic phaseswere washed with IM aqueous citric acid solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure togive ethyl (2S)-3-(2-methoxyphenyl)-2-(p-tolylsulfonyloxy)propanoate. MS(EI, 70 eV) m/z (% relative intensity, [ion]): 65 (7), 77 (14), 91 (49),123 (33), 133 (33), 165 (100), 207 (65), 307 (13), 512 (7, [M⁺])

Step B: Ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-(2-methoxyphenyl)propanoate

1 eq. Preparation 1c, 1.5 eq. ethyl(2S)-3-(2-methoxyphenyl)-2-(p-tolylsulfonyloxy) propanoate, 2 eq. K₂CO₃and DMSO (10 mL/mmol benzofurane derivative) were stirred at 60° C.under N₂ atmosphere until no further conversion was observed. Then itwas diluted with brine, neutralized with IM aqueous HCl solution andextracted with DCM. The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude product was purified via flash chromatography using heptane andEtOAc as eluents to give ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-(2-methoxyphenyl)propanoate.MS (EI, 70 eV) m/z (% relative intensity, [ion]): 91 (56), 133 (41), 165(100), 207 (93), 281 (26), 305 (9), 512 (3, [M⁺]), 514 (3, [M⁺])

Step C: Examples 61 and 62

Using General Procedure VI and ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-(2-methoxyphenyl)propanoateas the appropriate 3-bromo-benzofuran derivative and Preparation 3b asthe appropriate boronic acid derivative, Example 61 was obtained as theearlier eluting diastereoisomer. HRMS calculated for C₃₈H₃₈ClFN₂O₆:672.2402, found: 673.2465 (M+H). Example 62 was obtained as the latereluting diastereoisomer. HRMS calculated for C₃₈H₃₈ClFN₂O₆: 672.2402,found: 673.2486 (M+H).

Example 63:(2R)-2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid and Example 64:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A: Ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[2-(2-methoxyphenyl)pyrimidin-4-yl]oxyphenyl]propanoate

Using General Procedure V and Preparation 1c as the appropriatebenzofuran-4-ol derivative and Preparation 2d as the appropriate lacticester derivative, ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[2-(2-methoxyphenyl)pyrimidin-4-yl]oxyphenyl]propanoate was obtained. MS: (M+H)⁺=699.2

Step B: Examples 63 and 64

Using General Procedure VI and ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[2-(2-methoxyphenyl)pyrimidin-4-yl] oxyphenyl]propanoate as theappropriate 3-bromo-benzofuran derivative and Preparation 3b as theappropriate boronic acid derivative, Example 63 was obtained as theearlier eluting diastereoisomer. HRMS calculated for C₄₉H₄₆ClFN₄O₇:856.3039, found: 429.1582 (M+2H). Example 64 was obtained as the latereluting diastereoisomer. HRMS calculated for C₄₉H₄₆ClFN₄O₇: 856.3039,found: 429.1604 (M+2H).

Example 65:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoic Acid Step A: Ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate

Using General Procedure V and Preparation 1c as the appropriatebenzofuran-4-ol derivative and Preparation 2h as the appropriate lacticester derivative, ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoatewas obtained. MS: (M+Na)⁺=604.4

Step B: Example 65

Using General Procedure VI and ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate as the appropriate3-bromo-benzofuran derivative and Preparation 3b as the appropriateboronic acid derivative, Example 65 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₃₉H₃₇ClF₄N₂O₆: 740.2276, found:741.2372 (M+H).

Example 66:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-fluoro-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-[2-(2,2,2-trifluoroethoxy)phenyl] propanoic Acid Step A: Ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate

Using General Procedure V and Preparation 1d as the appropriatebenzofuran-4-ol derivative and Preparation 2h as the appropriate lacticester derivative, ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate was obtained. 1H NMR (400 MHz, DMSO-d₆): 8.07 (m, 2H),7.43 (m, 3H), 7.27 (m, 2H), 7.11 (m, 1H), 6.98 (m, 1H), 6.55 (dd, 1H),5.23 (m, 1H), 4.82 (q, 2H), 4.12 (q, 2H), 3.37 (m, 1H), 3.25 (m, 1H),1.10 (t, 3H)

Step B: Example 66

Using General Procedure VI and ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate as theappropriate 3-bromo-benzofuran derivative and Preparation 3b as theappropriate boronic acid derivative, Example 66 was obtained as thelater eluting diastereoisomer. HRMS calculated for C₃₉H₃₆ClF₅N₂O₆:758.2182, found: 759.2244 (M+H).

Example 67:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-fluoro-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A: Ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

Using General Procedure V and Preparation 1d as the appropriatebenzofuran-4-ol derivative and Preparation 2d as the appropriate lacticester derivative, ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate was obtained. 1H NMR (400 MHz,DMSO-d₆): 8.86 (d, 1H), 8.05 (m, 2H), 7.61 (d, 1H), 7.52 (dd, 1H),7.48-7.38 (m, 4H), 7.25 (m, 1H), 7.21 (m, 1H), 7.12 (m, 2H), 7.03 (td,1H), 6.94 (td, 1H), 6.67 (dd, 1H), 5.40 (m, 1H), 5.26 (s, 2H), 4.15 (q,2H), 3.75 (s, 3H), 3.56 (m, 1H), 3.30 (m, 1H), 1.12 (t, 3H)

Step B: Example 67

Using General Procedure VI and ethyl(2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoateas the appropriate 3-bromo-benzofuran derivative and Preparation 3b asthe appropriate boronic acid derivative, Example 67 was obtained as thelater eluting diastereoisomer. HRMS calculated for C₄₉H₄₅ClF₂N₄O₇:874.2945, found: 438.1543 (M+2H).

Example 68:(2R)-2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-methyl-H-indol-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid and Example 69:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-methyl-1H-indol-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A:1-(benzenesulfonyl)-4-benzyloxy-indole

7.0 g 4-benzyloxy-1H-indole (31.35 mmol) was dissolved in 60 mL dry DMFand 1.317 g NaH (32.92 mmol, 60% on mineral oil) was added at 0° C. Themixture was stirred for 1 hour, then 6.09 g benzenesulfonyl chloride(34.48 mmol) was added dropwise and the mixture was stirred at 0° C.until no further conversion was observed. Then it was diluted with waterand extracted with DCM. The combined organic phases were dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure and purified via flash chromatography using heptane and EtOAcas eluents to obtain 1-(benzenesulfonyl)-4-benzyloxy-indole.

1H NMR (400 MHz, DMSO-d₆) δ: 7.97 (d, 2H), 7.72 (d, 1H), 7.69 (t, 1H),7.59 (t, 2H), 7.54 (d, 1H), 7.47 (d, 2H), 7.39 (t, 2H), 7.33 (d, 1H),7.27 (t, 1H), 6.89 (d, 1H), 6.85 (d, 1H), 5.20 (s, 2H) MS (EI, 70 eV)m/z (% relative intensity, [ion]): 77 (32), 91 (100), 141 (18), 222 (6),272 (11), 363 (10, [M⁺])

Step B: 1-(benzenesulfonyl)-4-benzyloxy-2-iodo-indole

5.08 g 1-(benzenesulfonyl)-4-benzyloxy-indole (13.98 mmol) was dissolvedin 140 mL dry THF. 8.54 mL LDA solution (15.38 mmol, 1.8M inTHF-heptane-ethylbenzene) was added at −78° C. and the mixture wasstirred for 1 hour. Then 4.26 g iodine (16.8 mmol) was added and themixture was stirred for 1 hour at −78° C. The mixture was quenched withsaturated aqueous NH₄Cl solution, extracted with EtOAc. The combinedorganic phases were washed with aqueous Na₂SO₃ solution and water, thendried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents to obtain1-(benzenesulfonyl)-4-benzyloxy-2-iodo-indole. 1H NMR (400 MHz, DMSO-d₆)δ: 7.86 (dd, 2H), 7.75 (d, 1H), 7.70 (d, 1H), 7.61 (t, 2H), 7.47 (dd,2H), 7.39 (t, 2H), 7.33 (d, 1H), 7.23 (t, 1H), 7.18 (s, 1H), 6.90 (d,1H), 5.20 (s, 2H)

Step C: 1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)indole

5.8 g 1-(benzenesulfonyl)-4-benzyloxy-2-iodo-indole (11.86 mmol) and3.16 g 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)fluorobenzene(14.22 mmol) were dissolved in 75 mL THF, then 7.73 g Cs₂CO₃ (23.72mmol), 420 mg Ataphos (0.59 mmol) and 25 mL water were added and themixture was stirred at 70° C. under N₂ atmosphere until no furtherconversion was observed. The mixture was then concentrated under reducedpressure and purified via flash chromatography using heptane and EtOAcas eluents to obtain1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)indole. 1H NMR (400MHz, DMSO-d₆) δ: 7.79 (d, 1H), 7.67 (m, 1H), 7.60-7.48 (m, 6H),7.43-7.25 (m, 8H), 7.00 (d, 1H), 5.57 (s, 1H), 5.22 (s, 2H)

Step D: 1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole

4.92 g 1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)indole (10.75mmol), 3.69 g Ag₂SO₄ (11.83 mmol) and 3.0 g iodine (11.83 mmol) werestirred in 100 mL EtOH at r.t. until no further conversion was observed.Then the mixture was concentrated under reduced pressure and purifiedvia flash chromatography using heptane and EtOAc as eluents to obtain1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole. MS:(M+H)⁺=584.2

Step E:1-(benzenesulfonyl)-4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole

5.5 g 1-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole(9.42 mmol), 4.46 g Preparation 3b (11.31 mmol), 6.14 g Cs₂CO₃ (18.84mmol) and 354 mg Ataphos (0.5 mmol) were dissolved in 100 mL THF:water3:1 and stirred at 70° C. under N₂ until no further conversion wasobserved. The mixture was concentrated under reduced pressure andpurified via flash chromatography using heptane, EtOAc and MeOH aseluents to obtain1-(benzenesulfonyl)-4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.85 (d, 1H), 7.67 (t, 1H), 7.61-6.90 (m,2H), 7.53-7.47 (m, 4H), 7.4 (t, 1H), 7.20-7.07 (m, 5H), 6.96 (d, 1H),6.77 (d, 1H), 6.73 (d, 1H), 6.66 (d, 2H), 4.96 (d, 1H), 4.86 (d, 1H),4.09 (m, 1H), 4.00 (m, 1H), 3.34 (br s, 4H), 2.75 (t, 2H), 2.58 (br s,4H), 2.30 (s, 3H), 1.81 (s, 3H)

MS: (M+H)⁺=724.2

Step F:4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1H-indole

6.5 g1-(benzenesulfonyl)-4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole(8.97 mmol) was dissolved in 100 mL THF and 100 mL MeOH, then 28.3 gBa(OH)₂×8 H₂O (89.7 mmol) was added and the mixture was stirred at 70°C. until no further conversion was observed. The mixture was thenfiltered, the filtrate was concentrated under reduced pressure andpurified via flash chromatography using DCM and MeOH as eluents toobtain4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1H-indole.MS: (M+H)⁺=584.2

Step G:4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indole

1.626 g4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1H-indole(2.78 mmol) was dissolved in 25 mL dry DMF and cooled to 0° C. Then 123mg NaH (3.06 mmol, 60% on mineral oil) was added and the mixture wasstirred for 1 hour. Then 395 mg methyl iodide (2.78 mmol) was added andthe mixture was stirred for 1 hour. The mixture was then poured intowater and extracted with DCM. The combined organic phases were washedwith brine, dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure. The crude product was purified via flashchromatography using DCM and MeOH as eluents to obtain4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indole.

1H NMR (400 MHz, DMSO-d₆) δ: 7.31 (dd, 2H), 7.24-7.10 (m, 7H), 6.97 (d,1H), 6.83-6.76 (m, 3H), 6.68 (dd, 1H), 5.01 (d, 1H), 4.93 (d, 1H), 4.14(m, 1H), 4.06 (m, 1H), 3.63 (s, 3H), 3.10-2.60 (br s, 8H), 2.84 (br s,2H), 2.58 (s, 3H), 2.04 (s, 3H)

Step H:3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indol-4-ol

1.6 g4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indole(2.68 mmol) was dissolved in 10 mL DCM and 1 eq.

HBr (33% solution in AcOH) was added. The mixture was stirred at r.t.until no further conversion was observed. The mixture was then dilutedwith 10% aqueous K₂CO₃ solution and extracted with DCM. The combinedorganic phases were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified via flash chromatography using DCM and MeOH as eluents,then via preparative reversed phase chromatography using 25 mM aqueousNH₄HCO₃ solution and MeCN as eluents to obtain3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indol-4-ol.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, 1H), 7.29-7.15 (m, 4H), 7.06-6.92(m, 2H), 6.86 (d, 1H), 6.78 (d, 1H), 6.38 (dd, 1H), 4.07 (m, 2H), 3.58(s, 3H), 2.70 (t, 2H), 2.58-2.40 (br s, 4H), 2.40-2.19 (br s, 4H), 2.19(s, 3H), 2.09 (s, 3H)

MS: (M+H)⁺=508.2

Step I: Ethyl(2S)-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]-2-(p-tolylsulfonyloxy)propanoate

3.668 g Preparation 2d (8.97 mmol) was dissolved in 12 mL pyridine and1.97 g TsCl (10.31 mmol) was added at 0° C. The mixture was stirred atr.t. until no further conversion was observed. Then the mixture wasdiluted with water and extracted with EtOAc. The combined organic phaseswere washed with IM aqueous citric acid solution, dried over MgSO₄,filtered and the filtrate was concentrated under reduced pressure togive ethyl(2S)-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]-2-(p-tolylsulfonyloxy)propanoate.

1H NMR (400 MHz, DMSO-d₆) δ: 8.93 (d, 1H), 7.58 (dd, 1H), 7.52-7.43 (m,2H), 7.43-7.34 (m, 2H), 7.26-7.15 (m, 4H), 7.13-7.04 (m, 2H), 6.93-6.83(m, 2H), 5.12 (d, 1H), 5.03-4.92 (m, 2H), 4.01 (q, 2H), 3.79 (s, 3H),3.26 (dd, 1H), 3.01 (dd, 1H), 2.36 (s, 3H), 1.12 (t, 3H)

MS: (M+H)⁺=563.2

Step J: Examples 68 and 69

60 mg3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-1-methyl-indol-4-ol (0.12 mmol), 101 mg ethyl(2S)-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]-2-(p-tolylsulfonyloxy)propanoate(0.18 mmol) and 80 mg Cs₂CO₃ (0.24 mmol) were dissolved in 2 mL dry DMFand stirred at 50° C. until no further conversion was observed. Then 2eq. LiOH×H₂O was added and mixture was stirred at r.t. until no furtherconversion was observed. The mixture was concentrated and purified bypreparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃solution and MeCN as eluents to obtain Example 68 as the earlier elutingdiastereoisomer. HRMS calculated for C₅₀H₄₉ClFN₅O₆: 869.3355, found:435.6743 (M+2H). Example 69 was obtained as the later elutingdiastereoisomer. HRMS calculated for C₅₀H₄₉ClFN₅O₆: 869.3355, found:435.6767 (M+2H).

Example 70:N-[3-(3-chloro-2-methylphenyl)thieno[3,2-c]pyridin-4-yl]-D-phenylalanineStep A: 4-bromo-N-(dimethoxymethyl)thiophene-3-carboxamide

5.01 g 4-bromothiophene-3-carboxylic acid (24.2 mmol) was dissolved in25 mL isopropyl acetate and 17.9 mL SOCl₂ (242 mmol) was added and themixture was stirred at 50° C. for 2 hours. Then the excess SOCl₂ wasdistilled and the residue was dissolved in 25 mL isopropyl acetate andcooled to 10° C. 10.6 mL DIPEA (60.5 mmol) and 4.0 mL aminoacetaldehydedimethyl acetal (36.3 mmol) were added. The mixture was allowed to warmup to r.t. and stirred under N₂ atmosphere overnight. The mixture wasdiluted with 10% aqueous H₃PO₄ solution and extracted with isopropylacetate. The combined organic phases were washed with 10% aqueous KH₂PO₄solution and brine, then dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure to obtain4-bromo-N-(dimethoxymethyl)thiophene-3-carboxamide.

1H NMR (400 MHz, DMSO-d₆) δ: 8.36 (t, 1H), 7.93 (d, 1H), 7.72 (d, 1H),4.48 (t, 1H), 3.31-3.28 (m, 8H)

MS (M+H): 294.0

Step B: 3-bromo-5H-thieno[3,2-c]pyridin-4-one

32 mg 4-bromo-N-(dimethoxymethyl)thiophene-3-carboxamide (0.102 mmol)was dissolved in 1 mL PPA and stirred at 100° C. under argon atmosphereuntil no further conversion observed. The mixture was then poured intoice, the formed precipitate was filtered and washed with water to obtain3-bromo-5H-thieno[3,2-c]pyridin-4-one. MS (M+H): 229.9

Step C: 3-bromo-4-chloro-thieno[3,2-c]pyridine

1.06 g 3-bromo-5H-thieno[3,2-c]pyridin-4-one (4.4 mmol), 560 μLN,N-dimethylaniline (4.4 mmol) and 8.37 mL POCl₃ (88 mmol) were stirredat 100° C. until no further conversion observed. The reaction mixturewas then poured into ice and extracted with DCM. The combined organicphases were washed with saturated aqueous NaHCO₃ solution and brine,dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents to obtain3-bromo-4-chloro-thieno[3,2-c]pyridine. MS (M+H): 247.9

Step D: 3,4-dibromothieno[3,2-c]pyridine

735 mg 3-bromo-4-chloro-thieno[3,2-c]pyridine (2.8 mmol) and 2.288 gbromotrimethylsilane (14.5 mmol) were dissolved in 15 mL propionitrileand stirred at 100° C. until no further conversion observed. Thereaction mixture was then concentrated under reduced pressure andpurified via preparative reversed phase chromatography using 40 mMaqueous NH₄OAc solution (pH=4, adjusted with AcOH) and MeCN as eluentsto obtain 3,4-dibromothieno[3,2-c]pyridine. MS (M+H): 291.8

Step E:(2R)-2-[(3-bromothieno[3,2-c]pyridin-4-yl)amino]-3-phenyl-propanoic Acid

340 mg 3,4-dibromothieno[3,2-c]pyridine (1.16 mmol) and 718 mgD-phenylalanine (4.35 mmol) were dissolved in 7.5 mL sulfolane, then 421mg potassium fluoride (7.25 mmol) and 2.23 g4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (5.8 mmol)were added and the mixture was stirred at 175° C. under argon atmosphereuntil no further conversion was observed. The reaction mixture wasdirectly injected and purified via preparative reversed phasechromatography using 40 mM aqueous NH₄OAc solution (pH=4, adjusted withAcOH) solution and MeCN as eluents to obtain (2R)-2-[(3-bromothieno[3,2-c]pyridin-4-yl)amino]-3-phenyl-propanoic acid.

Step F: Example 70

189 mg (2R)-2-[(3-bromothieno[3,2-c]pyridin-4-yl)amino]-3-phenyl-propanoic acid (0.5 mmol), 341 mg(3-chloro-2-methylphenyl)boronic acid (2 mmol) were dissolved in 3.5 mLDME, then 72 mg butyldi-1-adamantylphosphine (0.2 mmol), 22 mg Pd(OAc)₂(0.1 mmol) and 389 mg TBAOH (1.5 mmol) were added and the mixture wasstirred at 100° C. under argon atmosphere until no further conversionwas observed. Then the mixture was poured into icy water, extracted withMTBE. The aqueous phase was acidified to pH 2 and extracted with DCM.The combined organic phases were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified via preparative reversed phase chromatography using 25 mMaqueous NH₄HCO₃ solution and MeCN as eluents to obtain Example 70. HRMScalculated for C₂₃H₁₉ClN₂O₂S: 422.0856, found: 423.0937 and 423.0919 forthe two diastereomers (M+H).

Example 71:(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Step A:2-chloro-3-[2-(4-fluorophenyl)ethynyl]pyridine

In a dry flask 3.85 g 3-bromo-2-chloro-pyridine (20 mmol), 0.23 g CuI(1.2 mmol), 0.42 g PdCl₂(PPh₃)₂ (0.6 mmol) were added in 40 mL dry TEA.After stirring for 10 minutes, 2.64 g 1-ethynyl-4-fluoro-benzene (22mmol) was added and the solution was heated to 100° C. and stirredovernight. The reaction mixture was cooled down, diluted with water andthen it was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via flash chromatography using heptane and EtOAc aseluents to obtain 2-chloro-3-[2-(4-fluorophenyl)ethynyl]pyridine. 1H NMR(500 MHz, DMSO-d₆) δ 8.44 (dd, 1H), 8.14 (dd, 1H), 7.68 (t, 2H), 7.51(dd, 1H), 7.33 (t, 2H)

Step B: 2-(4-fluorophenyl)thieno[2,3-b]pyridine

2.95 g 2-chloro-3-[2-(4-fluorophenyl)ethynyl]pyridine (12.7 mmol) and3.97 g Na₂S (51 mmol) were placed in a 250 mL flask. 120 mL DMF wasadded and the mixture was stirred at 130° C. for 2 hours. Then thereaction mixture was cooled down, diluted with water and then it wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via flash chromatography using heptane and EtOAc aseluents to obtain 2-(4-fluorophenyl)thieno[2,3-b] pyridine. MS (M+H):230.2

Step C: 2-(4-fluorophenyl)thieno[2,3-b]pyridine N-oxide

1.94 g 2-(4-fluorophenyl)thieno[2,3-b]pyridine (8.4 mmol) was dissolvedin DCM (50 mL) and cooled to 0° C. 3.12 g MCPBA (12.6 mmol) was addedportionwise and stirred at r.t. for 6 hours. Then it was concentratedunder reduced pressure and the crude product was purified via flashchromatography using DCM and methanol as eluents. MS (M+H): 246.2

Step D: 4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine

1.56 g 2-(4-fluorophenyl)-7-oxido-thieno[2,3-b]pyridin-7-ium (6.4 mmol)was dissolved in 50 mL CHCl₃. 15.7 mL POCl₃ (25.76 g, 168 mmol) wasadded and the reaction mixture was stirred at reflux temperature for 3hours. Then it was cooled down, ice and saturated aqueous NaHCO₃ wasadded and it was extracted with CHCl₃. The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified via flash chromatography using DCM andmethanol as eluents to obtain4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine. MS (M+H): 264.0

Step E: 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine

1.15 g Br₂ (7.2 mmol) was added dropwise to a mixture of 1.46 g4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine (5.5 mmol), 0.52 gK₂HPO₄ (3.0 mmol), 0.46 g NaHCO₃ (5.5 mmol) and 1.12 g MgSO₄ (9.2 mmol)in 20 mL CHCl₃. The mixture was stirred overnight at reflux temperature.Then, the reaction was cooled down and filtered. The filtrate wasconcentrated under reduced pressure. The crude product was purified viaflash chromatography using DCM and methanol as eluents to obtain3-bromo-4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine. ¹H NMR (500MHz, DMSO-d₆) δ 8.59 (d, 1H), 7.76 (m, 2H), 7.71 (d, 1H), 7.42 (m, 2H)

Step F: 3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-ol

The mixture of 0.206 g3-bromo-4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine (0.6 mmol),0.492 g sodium acetate (6 mmol), 12 mL AcOH and 0.18 mL H₂O was heatedat 150° C. via MW irradiation for 5 hours. Water was added and theproduct was collected by filtration. ¹H NMR (500 MHz, DMSO-d₆) δ 11.63(br s, 1H), 8.30 (br s, 1H), 7.72 (m, 2H), 7.38 (m, 2H), 6.87 (br s, 1H)

Step G: Ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

0.324 g 3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-ol (1 mmol),0.613 g Preparation 2d (1.5 mmol), 0.691 g DTAD (3 mmol) and 0.787 gPPh₃ (3 mmol) were dissolved in 10 mL dry THF under N₂ atmosphere andthe mixture was stirred at r.t. until no further conversion wasobserved. The solvent was then removed under reduced pressure, theresidue was purified via flash chromatography using heptane and EtOAc aseluents to give ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate.¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (d, 1H), 8.33 (d, 1H), 7.72 (m, 2H),7.61 (d, 1H), 7.51 (dd, 1H), 7.45 (td, 1H), 7.44 (d, 1H), 7.39 (m, 2H),7.25 (td, 1H), 7.14 (d, 1H), 7.10 (d, 1H), 7.03 (td, 1H), 6.93 (t, 1H),6.88 (d, 1H), 5.55 (dd, 1H), 5.30 (d, 1H), 5.26 (d, 1H), 4.16 (m, 2H),3.75 (s, 3H), 3.58 (dd, 1H), 3.35 (dd, 1H), 1.13 (t, 3H)

Step H: Example 71

0.288 g(2R)-2-[3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.4 mmol), 0.472 g Preparation 3b (1.2 mmol), 0.028 g Ataphos (0.004mmol) and 0.392 g Cs₂CO₃ (1.2 mmol) were dissolved in a mixture ofdioxane (4 mL) and water (3 mL) and stirred under N₂ at 70° C. until nofurther conversion was observed. Then the mixture was diluted with waterand extracted with DCM. The combined organic phases were dried overNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified was purified via flash chromatography using DCM and methanol aseluents. The obtained intermediate was dissolved in a mixture of dioxane(7 mL) and water (7 mL) and 0.168 g LiOH×H₂O (4 mmol) was added. Themixture was stirred at r.t. until no further conversion was observed.Then it was diluted with brine, neutralized with 2M aqueous HCl,extracted with DCM. The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thediastereoisomers were purified and separated by preparative reversedphase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN aseluents. The diastereomer eluting later was collected as Example 71.HRMS calculated for C₄₈H₄₅ClFN₅O₆S: 873.2763; found 437.6441 (M+2H).

Example 72:(2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoicAcid Step A: Ethyl 2-amino-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate

The solution of 3330 mg ethyl 3-amino-3-imino-propanoate (20 mmol) and4340 mg 2-bromo-1-(4-fluorophenyl)ethanone (20 mmol) in 40 mL ethanolwas stirred at r.t. for 30 minutes, then 20 mL IM NaOEt solution inethanol (20 mmol) was added at 0° C., then it was stirred at 60° C. for90 minutes. Additional 13 mL IM NaOEt solution in ethanol (13 mmol) wasadded at room temperature and it was stirred at 60° C. for further 1hour. The reaction mixture was concentrated under reduced pressure,diluted with 40 mL water then it was extracted with ethyl acetate. Thecombined organic phase was dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The residue was purified viaflash chromatography using heptane and EtOAc as eluents to obtain ethyl2-amino-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. 1H NMR (400 MHz,DMSO-d₆) δ: 10.75 (br s, 1H), 7.52 (m, 2H), 7.14 (m, 2H), 6.44 (d, 1H),5.68 (br s, 2H), 4.14 (q, 2H), 1.25 (t, 3H)

Step B: 6-(4-fluorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one

The solution of 6.83 g ethyl2-amino-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (27.5 mmol) and 12mL formic acid in 50 mL formamide and 24 mL DMF was stirred at 160° C.for 16 hours in a sealed reaction vessel. The reaction mixture wascooled to room temperature; 150 mL 2-propanol was added. The precipitatewas filtered, washed with heptane, then it was dried under reducedpressure to obtain6-(4-fluorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one. 1H NMR (400MHz, DMSO-d₆) δ: 12.36 (br s, 1H), 11.88 (br s, 1H), 7.88 (m, 3H), 7.27(t, 2H), 6.93 (s, 1H)

Step C: 4-chloro-6-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

The solution of 4.50 g6-(4-fluorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one (19.6 mmol)in 46 mL POCl₃ (491 mmol) was stirred at 90° C. for 3 hours. It wasconcentrated under reduced pressure, the residue was poured onto ice.The pH was adjusted to 7 using solid K₂CO₃, then the mixture wasextracted with ethyl acetate. The combined organic phase was washed withbrine, then it was dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure to give4-chloro-6-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400MHz, DMSO-d₆) δ: 13.04 (br s, 1H), 8.60 (s, 1H), 8.08 (m, 2H), 7.37 (t,2H), 7.10 (d, 1H)

Step D: 4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine

To the solution of 1.87 g4-chloro-6-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (7.55 mmol) in38 mL DMF 1.286 g MeI (9.06 mmol) then 1.15 g K₂CO₃ (8.30 mmol) wasadded and it was stirred at r.t. for 1 hour. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with brine,and it was extracted with dichloromethane. The combined organic phasewas dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure, then the residue was purified via flash chromatographyusing heptane and ethyl acetate as eluents to obtain4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine. 1H NMR(400 MHz, DMSO-d₆) δ: 8.69 (s, 1H), 7.79 (m, 2H), 7.42 (m, 2H), 6.80 (s,1H), 3.83 (s, 3H)

Step E:5-bromo-4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine

To the solution of 1.36 g4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine (5.20mmol) in 16 mL acetic acid 5.46 mL IM Br₂ solution in acetic acid (5.46mmol) was added dropwise at 0° C., then the reaction mixture was stirredat r.t. for 30 minutes. The reaction mixture was concentrated underreduced pressure, then the residue was diluted with saturated aqueousNaHCO₃ solution and it was extracted with ethyl acetate. The combinedorganic phase was dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viaflash chromatography using heptane and ethyl acetate as eluents toobtain5-bromo-4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine.1H NMR (400 MHz, DMSO-d₆) δ: 8.73 (s, 1H), 7.70 (m, 2H), 7.47 (m, 2H),3.69 (s, 3H)

Step F: Ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

845 mg5-bromo-4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine(2.48 mmol), 1.27 g Preparation 2c (3.11 mmol) was dissolved in 10 mLDMF, then 2.43 g Cs₂CO₃ (7.44 mmol) was added and the mixture wasstirred at 60° C. for 6 hours. The reaction mixture was concentratedunder reduced pressure, it was diluted with brine, and then the mixturewas extracted with ethyl acetate. The combined organic phase was driedover MgSO₄, filtered and the filtrate was concentrated under reducedpressure, then the residue was purified via flash chromatography usingheptane and ethyl acetate as eluents to obtain ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate.MS (M+H): 712.0

Step G: Example 72

Using General Procedure II and ethyl(2R)-2-[5-bromo-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoateinstead of 5-bromo-furo[2,3-d]pyrimidyl-lactic ester, and usingPreparation 3b as the appropriate boronic acid derivative, Example 72was obtained as a mixture of diastereoisomers. HRMS calculated forC₄₈H₄₇ClFN₇O₆: 871.3260; found 436.6703 and 436.6710 (M+2H).

Example 73:2-{[3-{3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 74:2-{[3-{2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Example 75: 1-[(dimethylcarbamoyl)oxy]ethyl(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate

591 mg dimethylamine hydrochloride (7.25 mmol) and 1.20 mL pyridine(14.9 mmol) were dissolved in 18 mL dry DCM under nitrogen atmosphere,then the mixture was cooled to −78° C. and 990 mg 1-chloroethylchloroformate (6.9 mmol) was added. The reaction mixture was stirred at−78° C. until no further conversion was observed. The cold mixture wasfiltered and the filtrate was concentrated under reduced pressure (30mbar) using a 30° C. bath. Then it was dissolved in 2 mL dry DMF undernitrogen atmosphere, 60 mg Example 71 (0.069 mmol) and 223 mg Cs₂CO₃(0.55 mmol) were added and the reaction mixture was stirred at r.t.until no further conversion was observed. Then the mixture was dilutedwith brine, extracted with EtOAc. The combined organic layer was driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via reversed phasechromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluentsto obtain Example 75 as a mixture of diastereoisomers. HRMS calculatedfor C₅₃H₅₄ClFN₆O₈S: 988.3397; found: 495.1782 and 495.1772 (M+2H).

Example 76: 1-[(ethoxycarbonyl)oxy]ethyl(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate

668 mg EtOH (14.5 mmol) and 1.26 g pyridine (15.6 mmol) were dissolvedin 18 mL dry DCM under nitrogen atmosphere, then the mixture was cooledto −78° C. and 1.98 g 1-chloroethyl chloroformate (13.8 mmol) was added.The reaction mixture was stirred at −78° C. until no further conversionwas observed. The cold mixture was filtered and the filtrate wasconcentrated under reduced pressure (30 mbar) using a 30° C. bath. Thenit was dissolved in 2 mL dry DMF under nitrogen atmosphere, 60 mgExample 71 (0.069 mmol) and 223 mg Cs₂CO₃ (0.55 mmol) were added and thereaction mixture was stirred at r.t. until no further conversion wasobserved. Then the mixture was filtered and the filtrate was purifiedvia reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solutionand MeCN as eluents to obtain Example 76 as a mixture ofdiastereoisomers. HRMS calculated for C₅₃H₅₃ClFN₅O₉S: 989.3237; found:990.3342 and 990.3314 (M+H).

Example 77:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-hydroxy-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 78:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-4-hydroxy-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)butanoic Acid Example 79:2-O-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]-3,4-dideoxy-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)pentonic Acid Example 80:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-[2-({2-[5-(hydroxymethyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoicAcid Example 81:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-{2-[(2-{2-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoicAcid Example 82:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-{2-[(2-{4-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoicAcid Example 83:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-[2-({2-[3-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoicAcid Example 84:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanineStep A: ethyl(2R)-2-[[3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

343 mg 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[2,3-b]pyridine (Step Ein Example 71, 1.0 mmol) and 455 mg Preparation 2i (1.20 mmol) weredissolved in 5 mL dry DMSO, then 978 mg Cs₂CO₃ (3.0 mmol) was added andthe mixture was stirred under nitrogen atmosphere at 100° C. until nofurther conversion was observed. Then it was diluted with brine,neutralized with 2 M aqueous HCl solution, and extracted with DCM. Thecombined organic phase was dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure. Then it was dissolved 1.5 mL1.25 M HCl solution in EtOH, and the mixture was stirred at 60° C. untilthe ester formation was complete. Then it was carefully neutralized withsaturated aqueous NaHCO₃ solution, extracted with DCM. The combinedorganic phase was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viaflash chromatography using heptane and EtOAc as eluents.

1H NMR (500 MHz, DMSO-d₆) δ: 8.77 (d, 1H), 8.07 (d, 1H), 7.6 (m, 2H),7.52-6.88 (m, 8H), 7.37 (d, 1H), 7.34 (m, 2H), 7.05 (d, 1H), 6.57 (d,1H), 5.23/5.19 (d+d, 2H), 4.92 (m, 1H), 4.12 (m, 2H), 3.73 (s, 3H),3.44/3.25 (dd+dd, 2H), 1.14 (t, 3H)

HRMS calculated for C₃₆H₃₀BrFN₄O₄S: 712.1155; found: 357.0649 (M+2H).

Step B: ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

178 mg ethyl(2R)-2-[[3-bromo-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.249 mmol) and 107 mg Preparation 3a (0.4 mmol) were dissolved in 1 mL1,4-dioxane under nitrogen atmosphere, then 163 mg Cs₂CO₃ (0.50 mmol),0.5 mL water and 28 mg AtaPhos (0.04 mmol) were added and the mixturewas stirred in a microwave reactor at 111° C. for 15 minutes. Then itwas diluted with brine, neutralized with 2 M aqueous HCl solution, andextracted with DCM. The combined organic phase was dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude product was purified via flash chromatography using heptane andEtOAc as eluents to obtain ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoateas a mixture of atropoisomers. HRMS calculated for C₄₃H₃₆ClFN₄O₅S:774.2079; found: 388.1113 (M+2H).

Step C: Example 84

80 mg ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.103 mmol), 43 mg 2-(4-methylpiperazin-1-yl)ethanol (0.30 mmol), and79 mg PPh₃ (0.30 mmol) were dissolved in 1 mL dry toluene, then 69 mgDTAD (0.30 mmol) was added and the mixture was stirred at 50° C. undernitrogen atmosphere until no further conversion was observed. Then themixture was concentrated under reduced pressure and the residue waspurified via flash chromatography using EtOAc and MeOH as eluents. Theobtained ester derivative was dissolved in 1 mL THF, then 80 mg LiOH×H₂Oand 1 mL water were added and the mixture was stirred at r.t. until thehydrolysis was complete. Then it was diluted with brine, neutralizedwith 2 M aqueous HCl solution, and extracted with DCM. The combinedorganic phase was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viareversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution andMeCN as eluents to obtain Example 84 as a 7:3 mixture ofdiastereoisomers. HRMS calculated for C₄₈H₄₆ClFN₆O₅S: 872.2923; found:437.1540 and 437.1538 (M+2H).

Example 85:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Example 86:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineStep A: 3-bromo-4-chloro-2-iodo-thieno[3,2-c]pyridine

4.97 g 3-bromo-4-chloro-thieno[3,2-c]pyridine (20.0 mmol) was dissolvedin 50 mL dry THF under argon atmosphere and the mixture was cooled to−45° C. Then 22 mL Mg(TMP)ClxLiC1 solution (22 mmol, 1 M in THF) wasadded dropwise and the mixture was stirred for 1 hour at −45° C., then 1hour at 0° C., then it was cooled to −45° C. again.

Then 5.58 g iodine (22 mmol, dissolved in 20 mL dry, cold THF) was addeddropwise and the mixture was stirred at −45° C. for 2 hours. Then it wasallowed to warm up to r.t. and concentrated under reduced pressure. Theresidue was poured onto 300 mL brine, and extracted with EtOAc. Thecombined organic phase was washed with saturated aqueous Na₂SO₃solution, saturated aqueous NH₄Cl solution, then with water and thendried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using hexanes and EtOAc as eluents.

1H NMR (500 MHz, DMSO-d₆) δ: 8.27 (d, 1H), 8.17 (d, 1H)

HRMS calculated for C₇H₂BrClINS: 372.7824; found: 373.7916 (M+H).

Step B: 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[3,2-c]pyridine

2.62 g 3-bromo-4-chloro-2-iodo-thieno[3,2-c]pyridine (7.0 mmol) and 2.33g 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.5 mmol)were dissolved in 18 mL THF under argon atmosphere, then 6.84 g Cs₂CO₃(21 mmol), 18 mL water, 79 mg Pd(OAc)₂ (0.35 mmol) and 297 mg^(t)BuXPhos (0.70 mmol) were added and the mixture was stirred at 70° C.until no further conversion was observed. Then the volatiles wereevaporated under reduced pressure. The residue was diluted with waterand extracted with EtOAc. The combined organic phase was washed withsaturated aqueous NH₄Cl solution, then with brine and then dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usinghexanes and EtOAc as eluents.

1H NMR (500 MHz, DMSO-d₆) δ: 8.35 (d, 1H), 8.26 (d, 1H), 7.74 (dd, 2H),7.42 (t, 2H) HRMS calculated for C₁₃H₆BrClFNS: 340.9077; found: 341.9144(M+H).

Step C: ethyl(2R)-2-[[3-bromo-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

343 mg 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[3,2-c]pyridine (1.0mmol) and 455 mg Preparation 2i (1.20 mmol) were dissolved in 5 mL dryDMSO, then 978 mg Cs₂CO₃ (3.00 mmol) was added and the mixture wasstirred under nitrogen atmosphere at 100° C. until no further conversionwas observed. Then it was diluted with brine, neutralized with 2 Maqueous HCl solution, and extracted with DCM. The combined organic phasewas dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Then it was dissolved 1.5 mL 1.25 M HCl solution inEtOH, and the mixture was stirred at 60° C. until the ester formationwas complete. Then it was carefully neutralized with saturated aqueousNaHCO₃ solution, extracted with DCM. The combined organic phase wasdried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using heptane and EtOAc as eluents. HRMS calculated forC₃₆H₃₀BrFN₄O₄S: 712.1155; found: 713.1209 (M+H).

Step D: ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

31 mg ethyl(2R)-2-[[3-bromo-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.043 mmol) and 24 mg Preparation 3a (0.09 mmol) were dissolved in 0.5mL 1,4-dioxane under nitrogen atmosphere, then 33 mg Cs₂CO₃ (0.10 mmol),0.5 mL water and 9.4 mg AtaPhos (0.013 mmol) were added and the mixturewas stirred in a microwave reactor at 111° C. for 10 minutes. Then itwas diluted with brine, neutralized with 2 M aqueous HCl solution, andextracted with DCM. The combined organic phase was dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude product was purified via flash chromatography using heptane andEtOAc as eluents to obtain ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoateas a mixture of atropoisomers. HRMS calculated for C₄₃H₃₆ClFN₄O₅S:774.2079; found: 775.2134 (M+H).

Step E: Example 86

33 mg ethyl(2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.04 mmol), 15 mg 2-(4-methylpiperazin-1-yl)ethanol (0.10 mmol), and 26mg PPh₃ (0.10 mmol) were dissolved in 1 mL dry toluene, then 23 mg DTAD(0.10 mmol) was added and the mixture was stirred at 50° C. undernitrogen atmosphere until no further conversion was observed. Then themixture was concentrated under reduced pressure and the residue waspurified via flash chromatography using EtOAc and MeOH as eluents. Theobtained ester derivative was dissolved in 1 mL THF, then 80 mg LiOH×H₂Oand 1 mL water were added and the mixture was stirred at rt until thehydrolysis was complete. Then it was diluted with brine, neutralizedwith 2 M aqueous HCl solution, and extracted with DCM. The combinedorganic phase was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was purified viareversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution andMeCN as eluents to obtain Example 86 as a 10:3 mixture ofdiastereoisomers. HRMS calculated for C₄₈H₄₆ClFN₆O₅S: 872.2923; found:437.1549 and 437.1532 (M+2H).

Example 87:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-c]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Example 88:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 89:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 90:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 91:2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-c]pyridazin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 92:N-[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-c]pyridazin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 93:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)furo[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Example 94:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)furo[2,3-b]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 95:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)furo[3,2-c]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Example 96:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)furo[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 97a:2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid and Example 97b:2-[{(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicAcid Step A: 1-(2-bromo-1,1-dimethoxy-ethyl)-4-fluoro-benzene

8.68 g 2-bromo-1-(4-fluorophenyl)ethanone (40.0 mmol) was dissolved in80 mL MeOH, then 8.75 mL CH(OMe)₃ (80.0 mmol) and 380 mg TsOH×H₂O (2.00mmol) was added and the mixture was stirred at reflux temperature untilno further conversion was observed. Then it was concentrated underreduced pressure and diluted with Et₂O. It was washed with 10% aqueousK₂CO₃ solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. 1H NMR (250 MHz, CDCl₃) δ:7.53-7.44 (m, 2H), 7.11-7.01 (m, 2H), 3.60 (s, 2H), 3.22 (s, 6H)

Step B: 5-chloro-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidine

A high pressure reaction vessel made of steel was charged with 648 mg2-chloropyrimidin-4-amine (5.0 mmol), 1.58 g1-(2-bromo-1,1-dimethoxy-ethyl)-4-fluoro-benzene (6.0 mmol), 123 mgSc(OTf)₃ (0.25 mmol) and 50 mL MeCN and the mixture was stirred at 120°C. for 24 hours. Then it was diluted with DCM and washed with saturatedaqueous NaHCO₃ solution. The aqueous layer was extracted with DCM. Thecombined organic layer was dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The crude product was purifiedvia flash chromatography using hexanes and EtOAc as eluents. HRMScalculated for C₁₂H₇ClFN₃: 247.0312; found: 248.0397 (M+H).

Step C: 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidine

198 mg 5-chloro-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidine (0.80 mmol)was dissolved in 4.8 mL DMF then 142 mg NBS (0.80 mmol) was added andthe mixture was stirred at r.t. until the consumption of the startingmaterial. Then the mixture was poured onto saturated aqueous NaHCO₃solution and the formed precipitate was filtered, washed with water. Thecrude product was purified via flash chromatography using hexanes andEtOAc as eluents.

1H NMR (500 MHz, DMSO-d₆) δ: 8.03 (m, 2H), 7.90 (d, 1H), 7.73 (d, 1H),7.39 (m, 2H) HRMS calculated for C₁₂H₆BrClFN₃: 324.9418; found: 325.9496(M+H).

Step D: ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

102 mg 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidine(0.312 mmol) and 140 mg Preparation 2c (0.344 mmol) were dissolved in 3mL dry DMSO under nitrogen atmosphere, then 305 mg Cs₂CO₃ (0.936 mmol)was added and the mixture was stirred at r.t. until no further desiredconversion was observed. Then it was diluted with brine and water,neutralized with 2 M aqueous HCl solution, and extracted with DCM. Thecombined organic phase was dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure. The crude product was purifiedvia flash chromatography using heptane and EtOAc as eluents.

¹H NMR (500 MHz, DMSO-d₆) δ: 8.20 (d, 1H), 8.03 (m, 2H), 7.62 (d, 1H),7.56 (d, 1H), 7.50 (dd, 1H), 7.49 (dd, 1H), 7.42 (ddd, 1H), 7.35 (m,2H), 7.27 (ddd, 1H), 7.23 (d, 1H), 7.13 (d, 1H), 7.11 (d, 1H), 7.01 (td,1H), 6.96 (td, 1H), 5.80 (dd, 1H), 5.31/5.27 (d+d, 2H), 4.18/4.15 (m+m,2H), 3.75 (s, 3H), 3.62/3.36 (dd+dd, 2H), 1.12 (t, 3H)

HRMS calculated for C₃₅H₂₉BrFN₅O₅: 697.1336; found: 698.1419 (M+H).

Step E: ethyl(2R)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

150 mg ethyl(2R)-2-[3-bromo-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate(0.215 mmol) and 80.8 mg Preparation 3a (0.301 mmol) were dissolved in 1mL THF under nitrogen atmosphere, then 140 mg Cs₂CO₃ (0.430 mmol), 0.2mL water and 30.4 mg AtaPhos (0.043 mmol) were added and the mixture wasstirred in a microwave reactor at 100° C. for 5 minutes. Then themixture was diluted with brine, neutralized with 2 M aqueous HClsolution and extracted with DCM. The combined organic phase was driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The crude product was purified via flash chromatography usingheptane and EtOAc as eluents to obtain a mixture of diastereoisomers.HRMS calculated for C₄₂H₃₅ClFN₅O₆: 759.2260; found: 760.2370 and760.2344 (M+H).

Step F: Examples 97a and 97b

11.4 mg ethyl(2R)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.015 mmol), 7.2 mg2-(4-methylpiperazin-1-yl)ethanol (0.050 mmol), and 13.1 mg PPh₃ (0.050mmol) were dissolved in 1 mL dry toluene, then 11.5 mg DTAD (0.050 mmol)was added and the mixture was stirred at 50° C. under nitrogenatmosphere until no further conversion was observed. Then the mixturewas concentrated under reduced pressure and the residue was purified viaflash chromatography using EtOAc and MeOH as eluents. The obtained esterderivative was dissolved in 1 mL THF, then 42 mg LiOH×H₂O and 1 mL waterwere added and the mixture was stirred at r.t. until the hydrolysis wascomplete. Then it was diluted with brine, neutralized with 2 M aqueousHCl solution, and extracted with DCM. The combined organic phase wasdried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via reversed phasechromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.Example 97a was obtained as the earlier eluting diastereoisomer. HRMScalculated for C₄₇H₄₅ClFN₇O₆: 857.3104; found: 429.6626 (M+2H).

Example 97b was obtained as the later eluting diastereoisomer. HRMScalculated for C₄₇H₄₅ClFN₇O₆: 857.3104; found: 429.6638 (M+2H).

Example 98:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 99:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyrazin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 100:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyrazin-5-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanineExample 101:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 102:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-5-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanineStep A: 2-(4-fluorophenyl)-1H-imidazo[1,2-a]pyrimidin-5-one

10.0 g 2-amino-1H-pyrimidin-4-one (90.0 mmol) and 9.77 g2-bromo-1-(4-fluorophenyl) ethanone (45.0 mmol) were dissolved in 100 mLDMF and the mixture was stirred at 120° C. until no further conversionwas observed. Then it was concentrated under reduced pressure and wasdiluted with EtOAc. Celite was added and the volatiles were evaporatedunder reduced pressure. The mixture was purified via flashchromatography using heptane and EtOAc as eluents. The regioisomereluting earlier was collected as2-(4-fluorophenyl)-1H-imidazo[1,2-a]pyrimidin-5-one. 1H NMR (500 MHz,DMSO-d₆) δ: 12.98 (br s, 1H), 8.14 (s, 1H), 7.97 (m, 2H), 7.90 (d, 1H),7.27 (m, 2H), 5.57 (d, 1H)

Step B: 5-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine

1.36 g 2-(4-fluorophenyl)-1H-imidazo[1,2-a]pyrimidin-5-one (5.9 mmol)and 16.6 mL POCl₃ was stirred at 93° C. for 90 minutes, then the mixturewas cooled to r.t. and concentrated under reduced pressure. The residuewas poured onto icy-water. After the ice melted the formed precipitatewas filtered, washed with water. 1H NMR (500 MHz, DMSO-d₆) δ: 8.65 (s,1H), 8.55 (d, 1H), 8.17 (m, 2H), 7.45 (d, 1H), 7.33 (m, 2H)

Step C: 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine

715 mg 5-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine (2.89 mmol)was dissolved in 10 mL chloroform then 570 mg NBS (3.20 mmol) was addedand the mixture was stirred at r.t. until the consumption of thestarting material. Then the mixture was concentrated under reducedpressure and purified via flash chromatography using heptane and EtOAcas eluents.

¹H NMR (500 MHz, DMSO-d₆) δ: 8.52 (d, 1H), 8.10 (m, 2H), 7.39 (m, 2H),7.38 (d, 1H) HRMS calculated for C₁₂H₆BrClFN₃: 324.9418; found: 325.9481(M+H).

Step D:5-chloro-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine

620 mg 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine (1.93mmol) and 2.37 g Preparation 3b (6.0 mmol) were dissolved in 10 mL THFunder nitrogen atmosphere, then 1.30 g Cs₂CO₃ (4.00 mmol), 3 mL waterand 273 mg AtaPhos (0.386 mmol) were added and the mixture was stirredin a microwave reactor at 110° C. for 10 minutes. Then the mixture wasdiluted with brine and extracted with DCM. The combined organic phasewas dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified via flashchromatography using EtOAc and MeOH as eluents. LRMS calculated forC₂₆H₂₆Cl₂FN₅O: 513.15; found: 514.1 (M+H).

Step E: Example 102

341 mg5-chloro-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine(0.66 mmol) and 300 mg Preparation 2i (0.76 mmol) were dissolved in 3 mLdry DMSO under nitrogen atmosphere, then 652 mg Cs₂CO₃ (2.0 mmol) wasadded and the mixture was stirred in a microwave reactor at 160° C. for10 minutes. Then it was diluted with brine and water, neutralized with 2M aqueous HCl solution, and extracted with DCM. The combined organicphase was dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The crude product was purified via reversedphase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN aseluents to obtain Example 102 as a mixture of diastereoisomers. HRMScalculated for C₄₇H₄₆ClFN₈O₅: 856.3264; found: 429.1687 and 429.1705(M+2H).

Example 103:2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic Acid Example 104:N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-5-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalaninePharmacological Study Example A: Inhibition of McI-1 by the FluorescencePolarisation Technique

The relative binding potency of each compound was determined viaFluorescence Polarisation (FP). The method utilised a Fluoresceinlabelled ligand (Fluorescein-(3Ala-Ahx-A-REIGAQLRRMADDLNAQY-OH; mw2,765) which binds to the McI-1 protein (such that McI-1 corresponds tothe UniProtKB® primary accession number: Q07820) leading to an increasedanisotropy measured in milli-polarisation (mP) units using a reader. Theaddition of a compound which binds competitively to the same site as theligand will result in a greater proportion of unbound ligand in thesystem indicated by a decrease in mP units.

Method 1:

An 11 point serial dilution of each compound was prepared in DMSO and 2al transferred into flat bottomed, low binding, 384-well plate (finalDMSO concentration 5%). 38 al of buffer (10 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], 150 mM NaCl,0.05% Tween 20, pH 7.4), containing the Fluorescein labelled ligand(final concentration 1 nM) and McI-1 protein (final concentration 5 nM)was then added.

Assay plates were incubated ˜2 hours at room temperature before FP wasmeasured on a Biomek Synergy2 reader (Ex. 528 nm, Em. 640 nm, Cut off510 nm) and mP units calculated. The binding of increasing doses of testcompound was expressed as a percentage reduction in mP compared to awindow established between ‘5% DMSO only’ and ‘100% inhibition’controls. 11-point dose response curves were plotted with XL-Fitsoftware using a 4-Parameter Logistic Model (Sigmoidal Dose-ResponseModel) and the inhibitory concentrations that gave a 50% reduction in mP(IC₅₀) were determined. Results obtained using Method 1 are presented inTable 1 below; IC₅₀ of McI-1 inhibition obtained using Method 1 are notunderlined.

Method 2:

An 11 point serial dilution of each compound was prepared in DMSO and 2al transferred into flat bottomed, low binding, 384-well plate (finalDMSO concentration 5%). 38 al of buffer (20 mM Na₂HPO₄, 1 mM EDTA, 50 mMNaCl, pH 7.4), containing the Fluorescein labelled ligand (finalconcentration 10 nM) and McI-1 protein (final concentration 10 nM) wasthen added.

Assay plates were incubated ˜2 hours at room temperature before FP wasmeasured on a Biomek Synergy2 reader (Ex. 528 nm, Em. 640 nm, Cut off510 nm) and mP units calculated. The binding of increasing doses of testcompound was expressed as a percentage reduction in mP compared to awindow established between ‘5% DMSO only’ and ‘100% inhibition’ controls(50 aM unlabelled ligand). 11-point dose response curves were plottedwith XL-Fit software using a 4-Parameter Logistic Model (SigmoidalDose-Response Model) and the inhibitory concentrations that gave a 50%reduction in mP (IC₅₀) were determined. Results obtained using Method 2are presented in Table 1 below; IC₅₀ of McI-1 inhibition obtained usingMethod 2 are underlined.

The results show that the compounds of the invention inhibit interactionbetween the McI-1 protein and the fluorescent peptide describedhereinbefore.

Example B: In Vitro Cytotoxicity

The cytotoxicity studies were carried out on the H929 multiple myelomatumour line.

The cells are distributed onto microplates and exposed to the testcompounds for 48 hours.

The cell viability is then quantified by a colorimetric assay, theMicroculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).

The results are expressed in IC₅₀ (the concentration of compound thatinhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

TABLE 1 IC₅₀ of Mcl-1 inhibition (fluorescence polarisation test) and ofcytotoxicity for H929 cells IC₅₀ (M) Mcl-1 FP IC₅₀ (M) MTT H929 Example1 3.8E−09 2.41E−08 Example 2 6.0E−09 1.45E−08 Example 3 1.7E−08 3.64E−07Example 4 2.9E−08 3.29E−07 Example 5 1.5E−08 6.19E−07 Example 6 8.9E−09ND Example 7 1.1E−07 7.57E−07 Example 8 6.6E−09 1.78E−08 Example 98.6E−08 6.89E−08 Example 10 1.8E−05 ND Example 11 3.4E−05 ND Example 125.6E−07 ND Example 13 6.6E−07 ND Example 14 1.2E−05 ND Example 157.3E−06 ND Example 16 1.8E−06 ND Example 17 3.8E−06 ND Example 183.1E−06 ND Example 19 3.3E−06 ND Example 20 64.8% @ 50 μM ND Example 218.7E−06 ND Example 22 74.2% @ 50 μM ND Example 23 6.8E−06 ND Example 241.8E−05 ND Example 25 9.1E−06 ND Example 26 5.9E−06 ND Example 273.3E−07 ND Example 28 63.25% @ 50 μM  ND Example 29 8.5E−06 ND Example30 6.4E−06 ND Example 31 7.9E−07 ND Example 32 3.5E−06 ND Example 332.6E−07 ND Example 34 6.4E−06 ND Example 35 2.9E−07 ND Example 366.5E−06 ND Example 37 5.3E−07 ND Example 38   67% @ 50 μM ND Example 3977.75% @ 50 μM  ND Example 40 8.6E−07/3.3E−08 ND Example 41 1.3E−05 NDExample 42 4.5E−07 ND Example 43 66.9% @ 50 μM ND Example 44 2.5E−06 NDExample 45 1.8E−06 ND Example 46   71% @ 50 μM ND Example 47 1.1E−05 NDExample 48 5.9E−06 ND Example 49 3.9E−08 ND Example 50 65.85% @ 10 μM ND Example 51 3.6E−07/5.5E−09 1.10E−05 Example 52 1.6E−06 ND Example 532.2E−08 2.53E−08 Example 54 1.2E−07 ND Example 55 55.35% @ 10 μM  NDExample 56 4.7E−08 ND Example 57 1.7E−07 ND Example 58 51.9% @ 10 μM NDExample 59 3.6E−08 1.24E−06 Example 60 1.9E−08 5.68E−07 Example 61 52.8%@ 10 μM ND Example 62 8.2E−07 ND Example 63 1.7E−07 ND Example 647.4E−09 4.71E−08 Example 65 1.0E−06 ND Example 66 1.6E−06 ND Example 671.4E−08 8.36E−08 Example 68 1.2E−06 ND Example 69 2.4E−08 1.04E−07Example 70 13.55% @ 10 μM  ND Example 71 5.02E−09 9.08E−09 Example 721.55E−08  3.2E−08 Example 73 ND ND Example 74 ND ND Example 75 5.61E−077.55E−08 Example 76 1.34E−07 1.01E−08 Example 77 ND ND Example 78 ND NDExample 79 ND ND Example 80 ND ND Example 81 ND ND Example 82 ND NDExample 83 ND ND Example 84 5.45E−09 1.09E−08 Example 85 ND ND Example86 3.05E−08 3.59E−08 Example 87 ND ND Example 88 ND ND Example 89 ND NDExample 90 ND ND Example 91 ND ND Example 92 ND ND Example 93 ND NDExample 94 ND ND Example 95 ND ND Example 96 ND ND Example 97a   55% @10 μM 1.16E−05 Example 97b 4.10E−08 4.59E−07 Example 98 ND ND Example 99ND ND Example 100 ND ND Example 101 ND ND Example 102 nocurve >3.00E−05   Example 103 ND ND Example 104 ND ND Note: IC₅₀ ofMcl-1 inhibition obtained using Method 2 are underlined. ND: notdetermined For partial inhibitors, the percentage fluorescencepolarization inhibition for a given concentration of the test compoundis indicated. Accordingly, 45.1% @ 10 μM means that 45.1% fluorescencepolarization inhibition is observed for a concentration of test compoundequal to 10 μM.

Example C: Quantification of the cleaved form of PARP in vivo

The ability of the compounds of the invention to induce apoptosis, bymeasuring cleaved PARP levels, is evaluated in a xenograft model ofAMO-1 multiple myeloma cells. 1.10⁷ AMO-1 cells are graftedsub-cutaneously into immunosuppressed mice (SCID strain). 12 to 14 daysafter the graft, the animals are treated by intraveinous or oral routeswith the various compounds. After treatment, the tumour masses arerecovered and lysed, and the cleaved form of PARP is quantified in thetumour lysates.

The quantification is carried out using the “Meso Scale Discovery (MSD)ELISA platform” test, which specifically assays the cleaved form ofPARP. It is expressed in the form of an activation factor correspondingto the ratio between the quantity of cleaved PARP in the treated micedivided by the quantity of cleaved PARP in the control mice.

The results (presented in Table 2 below) show that the compounds of theinvention are capable of inducing apoptosis in AMO-1 tumour cells invivo.

TABLE 2 Quantification of the cleaved form of PARP in vivo PARP foldExample 1 157.5 Example 2 216.3 Example 8 55.4 Example 53 40.2 Example67 29.3 Example 72 15.7

Example D: Anti-Tumour Activity In Vivo

The anti-tumour activity of the compounds of the invention is evaluatedin a xenograft model of AMO-1 multiple myeloma cells.

1×10⁷ AMO-1 cells are grafted sub-cutaneously into immunosuppressed mice(SCID strain).

6 to 8 days after the graft, when the tumour mass has reached about 150mm³, the mice are treated with the various compounds in a daily schedule(5-day treatment). The tumour mass is measured twice weekly from thestart of treatment.

The compound of the invention has anti-tumour activity (tumourregression) in the AMO-1 multiple myeloma model with ΔT/C (qualificationparameter of the activity of a product, which is measured by subtractingthe median tumor volume on the day of last treatment from the mediantumor volume on the day of first treatment/tumour volume of theuntreated control group on the day of last treatment) of −27%. Theresults obtained show that the compounds of the invention inducesignificant tumour regression during the treatment period.

Example E: Pharmaceutical Composition: Tablets

1000 tablets containing a dose of 5 mg of 5 g a compound selected fromExamples 1 to 104 Wheat starch 20 g  Maize starch 20 g  Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

1. A method of treating a condition requiring a pro-apoptotic agent in asubject in need thereof, comprising administration of an effectiveamount of a compound of formula (I), its enantiomers, diastereoisomersand atropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base, alone or in combination with one or morepharmaceutically acceptable excipients:

wherein: A represents the group

in which 1 is linked to the W group and 2 is linked to the phenyl ring,wherein: the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₀ represents ahydrogen atom, a linear or branched (C₁-C₆)alkyl group, a linear orbranched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynylgroup, an arylalkyl(C₁-C₆) group, a cycloalkylalkyl(C₁-C₆) group, alinear or branched (C₁-C₆)polyhaloalkyl, -alkyl(C₁-C₆)—O—Cy₄, or thesubstituents of the pair (R₉, R₁₀), when grafted onto two adjacentcarbon atoms, together with the carbon atoms carrying them, form anaromatic or non-aromatic ring having from 5 to 7 ring members, whichring may contain from 1 to 3 heteroatoms selected from oxygen, sulphurand nitrogen, R₁₁ and R₁₁′ independently of one another represent ahydrogen atom, a linear or branched (C₁-C₆)alkyl group, or thesubstituents of the pair (R₁₁, R₁₁′), together with the nitrogen atomcarrying them, form an aromatic or non-aromatic ring having from 5 to 7ring members, which ring may contain, in addition to the nitrogen atom,from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,wherein the nitrogen may be substituted by a hydrogen atom or a linearor branched (C₁-C₆)alkyl group, R₁₂ represents -Cy₅,-Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆, -Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇,—C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁, —NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁₁,—SO₂—R₁₁, —C(O)—OR₁₁, or —NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′,independently of one another, represent a hydrogen atom, or anoptionally substituted linear or branched (C₁-C₆)alkyl group, R₁₄represents a hydrogen atom, a hydroxy group, or a hydroxy(C₁-C₆)alkylgroup, R_(a) represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R_(b) represents a —O—C(O)—O—R_(c) group, a—O—C(O)—NR_(c)R_(c)′ group, or a —O—P(O)(OR_(c))₂ group, R_(c) andR_(c)′, independently of one another, represent a hydrogen atom, alinear or branched (C₁-C₈)alkyl group, a cycloalkyl group, a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, a (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylgroup, or the substituents of the pair (R_(c), R_(c)′), together withthe nitrogen atom carrying them, form a non-aromatic ring having from 5to 7 ring members, which ring may contain, in addition to the nitrogenatom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, whereinthe nitrogen in question may be substituted by a linear or branched(C₁-C₆)alkyl group, Cy₁, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independentlyof one another, represent a cycloalkyl group, a heterocycloalkyl group,an aryl group, or a heteroaryl group, n is an integer equal to 0 or 1,wherein: “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenylgroup, “heteroaryl” means any mono- or bi-cyclic group composed of from5 to 10 ring members, having at least one aromatic moiety and containingfrom 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic groupcontaining from 3 to 10 ring members, “heterocycloalkyl” means any mono-or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation.
 2. The method according to claim 1,wherein: R₁ and R₂ independently of one another represent a halogenatom, a linear or branched (C₁-C₆)alkyl group, a hydroxy group, a linearor branched (C₁-C₆)alkoxy group, or the substituents of the pair (R₁,R₂), together with the carbon atoms carrying them, form an aromatic ringhaving from 5 to 7 ring members, which ring may contain from 1 to 3nitrogen atoms, R₃ represents a hydrogen atom, a halogen atom, a linearor branched (C₁-C₆)alkyl group, a hydroxy group, a linear or branched(C₁-C₆)alkoxy group, or —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, R₄ and R₅independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, R₆ and R₇ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a linear or branched (C₁-C₆)alkoxy group, a cyano group,a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, -alkyl(C₀-C₆)-Cy₁,—O-alkyl(C₁-C₆)—R₁₂, or —C(O)—NR₁₁R₁₁′, R₈ represents a hydrogen atom, alinear or branched (C₁-C₈)alkyl group, or a —CHR_(a)R_(b) group, R₉represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, -Cy₂, or a halogen atom, R₁₀ represents a hydrogenatom, a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, anarylalkyl(C₁-C₆) group, a cycloalkylalkyl(C₁-C₆) group, a linear orbranched (C₁-C₆)polyhaloalkyl, or -alkyl(C₁-C₆)—O—Cy₄, or thesubstituents of the pair (R₉, R₁₀), when grafted onto two adjacentcarbon atoms, together with the carbon atoms carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, R₁₁ and R₁₁′ independently of one another represent a hydrogenatom, a linear or branched (C₁-C₆)alkyl group, or the substituents ofthe pair (R₁₁, R₁₁′), together with the nitrogen atom carrying them,form a non-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen and nitrogen, wherein the nitrogen be substitutedby a linear or branched (C₁-C₆)alkyl group, R₁₂ represents -Cy₅ or-Cy₅-alkyl(C₀-C₆)-Cy₆, W represents a —NH— group or an oxygen atom,wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups sodefined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₁-C₆)alkoxy, hydroxy, oxo (or N-oxide where appropriate),—C(O)—OR′, —C(O)—NR′R″, —O—C(O)—NR′R″, —NR′R″, —O—P(O)(OR′)₂,—O—P(O)(O⁻M⁺)₂, linear or branched (C₁-C₆)polyhaloalkyl, halogen, or analdohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group and M⁺ represents a pharmaceuticallyacceptable monovalent cation.
 3. The method according to claim 1,wherein n is an integer equal to
 1. 4. The method according to claim 1,wherein the compound of formula (I) is compound of formula (I-a):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₁ and R₁₁′independently of one another represent a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, or the substituents of the pair (R₁₁,R₁₁′), together with the nitrogen atom carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the nitrogen may besubstituted by a hydrogen atom or a linear or branched (C₁-C₆)alkylgroup, R₁₂ represents -Cy₅, -Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆,-Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇, —C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁,—NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁, —SO₂—R₁₁, —C(O)—OR₁₁, or—NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′, independently of one another,represent a hydrogen atom, or an optionally substituted linear orbranched (C₁-C₆)alkyl group, R₁₄ represents a hydrogen atom, a hydroxygroup, or a hydroxy(C₁-C₆)alkyl group, R_(a) represents a hydrogen atomor a linear or branched (C₁-C₆)alkyl group, R_(b) represents a—O—C(O)—O—R_(c) group, a —O—C(O)—NR_(c)R_(c)′ group, or a—O—P(O)(OR_(c))₂ group, R_(c) and R_(c)′, independently of one another,represent a hydrogen atom, a linear or branched (C₁-C₈)alkyl group, acycloalkyl group, a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl group, or the substituents of the pair(R_(c), R_(c)′), together with the nitrogen atom carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen and nitrogen, wherein the nitrogen in question maybe substituted by a linear or branched (C₁-C₆)alkyl group, Cy₁, Cy₂,Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independently of one another, represent acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group, n is an integer equal to 0 or 1, wherein: “aryl” meansa phenyl, naphthyl, biphenyl, indanyl or indenyl group, “heteroaryl”means any mono- or bi-cyclic group composed of from 5 to 10 ringmembers, having at least one aromatic moiety and containing from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, “cycloalkyl”means any mono- or bi-cyclic non-aromatic carbocyclic group containingfrom 3 to 10 ring members, “heterocycloalkyl” means any mono- orbi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 5. The method according to claim 1, wherein thecompound of formula (I) is a compound of formula (I-b):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₁ and R₁₁′independently of one another represent a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, or the substituents of the pair (R₁₁,R₁₁′), together with the nitrogen atom carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the nitrogen may besubstituted by a hydrogen atom or a linear or branched (C₁-C₆)alkylgroup, R₁₂ represents -Cy₅, -Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)—NR₁-alkyl(C₀-C₆)-Cy₆,-Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇, —C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁,—NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁, —SO₂—R₁₁, —C(O)—OR₁₁, or—NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′, independently of one another,represent a hydrogen atom, or an optionally substituted linear orbranched (C₁-C₆)alkyl group, R₁₄ represents a hydrogen atom, a hydroxygroup, or a hydroxy(C₁-C₆)alkyl group, R_(a) represents a hydrogen atomor a linear or branched (C₁-C₆)alkyl group, R_(b) represents a—O—C(O)—O—R_(c) group, a —O—C(O)—NR_(c)R_(c)′ group, or a—O—P(O)(OR_(c))₂ group, R_(c) and R_(c)′, independently of one another,represent a hydrogen atom, a linear or branched (C₁-C₈)alkyl group, acycloalkyl group, a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl group, or the substituents of the pair(R_(c), R_(c)′), together with the nitrogen atom carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen and nitrogen, wherein the nitrogen in question maybe substituted by a linear or branched (C₁-C₆)alkyl group, Cy₁, Cy₂,Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independently of one another, represent acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group, n is an integer equal to 0 or 1, wherein: “aryl” meansa phenyl, naphthyl, biphenyl, indanyl or indenyl group, “heteroaryl”means any mono- or bi-cyclic group composed of from 5 to 10 ringmembers, having at least one aromatic moiety and containing from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, “cycloalkyl”means any mono- or bi-cyclic non-aromatic carbocyclic group containingfrom 3 to 10 ring members, “heterocycloalkyl” means any mono- orbi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 6. The method according to claim 1, wherein thecompound of formula (I) is a compound of formula (I-c):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₀ represents ahydrogen atom, a linear or branched (C₁-C₆)alkyl group, a linear orbranched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynylgroup, an arylalkyl(C₁-C₆) group, a cycloalkylalkyl(C₁-C₆) group, alinear or branched (C₁-C₆)polyhaloalkyl, or -alkyl(C₁-C₆)—O—Cy₄, or thesubstituents of the pair (R₉, R₁₀), when grafted onto two adjacentcarbon atoms, together with the carbon atoms carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, R₁₁ and R₁₁′ independently of one another represent a hydrogenatom, a linear or branched (C₁-C₆)alkyl group, or the substituents ofthe pair (R₁₁, R₁₁′), together with the nitrogen atom carrying them,form an aromatic or non-aromatic ring having from 5 to 7 ring members,which ring may contain, in addition to the nitrogen atom, from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, wherein thenitrogen may be substituted by a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R₁₂ represents -Cy₅,-Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆, -Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇,—C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁, —NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁,—SO₂—R₁₁, —C(O)—OR₁₁, or —NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′,independently of one another, represent a hydrogen atom, or anoptionally substituted linear or branched (C₁-C₆)alkyl group, R₁₄represents a hydrogen atom, a hydroxy group, or a hydroxy(C₁-C₆)alkylgroup, R_(a) represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R_(b) represents a —O—C(O)—O—R_(c) group, a—O—C(O)—NR_(c)R_(c)′ group, or a —O—P(O)(OR_(c))₂ group, R_(c) andR_(c)′, independently of one another, represent a hydrogen atom, alinear or branched (C₁-C₈)alkyl group, a cycloalkyl group, a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, a (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylgroup, or the substituents of the pair (R_(c), R_(c)′), together withthe nitrogen atom carrying them, form a non-aromatic ring having from 5to 7 ring members, which ring may contain, in addition to the nitrogenatom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, whereinthe nitrogen in question may be substituted by a linear or branched(C₁-C₆)alkyl group, Cy₁, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independentlyof one another, represent a cycloalkyl group, a heterocycloalkyl group,an aryl group, or a heteroaryl group, n is an integer equal to 0 or 1,wherein: “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenylgroup, “heteroaryl” means any mono- or bi-cyclic group composed of from5 to 10 ring members, having at least one aromatic moiety and containingfrom 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic groupcontaining from 3 to 10 ring members, “heterocycloalkyl” means any mono-or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 7. The method according to claim 6, wherein R₁₀represents hydrogen; methyl; isopropyl; 2,2,2-trifluoroethyl; benzyl;4-methoxybenzyl; phenethyl; 3-phenyl-propyl; cyclopropylmethyl;cyclopentylethyl; naphthalen-1-ylmethyl; 2-(naphthalen-1-yloxy)ethyl;but-2-yn-1-yl; prop-2-en-lyl; or but-3-en-1-yl.
 8. The method accordingto claim 1, wherein the compound of formula (I) is a compound of formula(I-d):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₀ represents ahydrogen atom, a linear or branched (C₁-C₆)alkyl group, a linear orbranched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynylgroup, an arylalkyl(C₁-C₆) group, a cycloalkylalkyl(C₁-C₆) group, alinear or branched (C₁-C₆)polyhaloalkyl, or -alkyl(C₁-C₆)—O—Cy₄, or thesubstituents of the pair (R₉, R₁₀), when grafted onto two adjacentcarbon atoms, together with the carbon atoms carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, R₁₁ and R₁₁′ independently of one another represent a hydrogenatom, a linear or branched (C₁-C₆)alkyl group, or the substituents ofthe pair (R₁₁, R₁₁′), together with the nitrogen atom carrying them,form an aromatic or non-aromatic ring having from 5 to 7 ring members,which ring may contain, in addition to the nitrogen atom, from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, wherein thenitrogen may be substituted by a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R₁₂ represents -Cy₅,-Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆, -Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇,—C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁, —NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁₁,—SO₂—R₁₁, —C(O)—OR₁₁, or —NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′,independently of one another, represent a hydrogen atom, or anoptionally substituted linear or branched (C₁-C₆)alkyl group, R₁₄represents a hydrogen atom, a hydroxy group, or a hydroxy(C₁-C₆)alkylgroup, R_(a) represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R_(b) represents a —O—C(O)—O—R_(c) group, a—O—C(O)—NR_(c)R_(c)′ group, or a —O—P(O)(OR_(c))₂ group, R_(c) andR_(c)′, independently of one another, represent a hydrogen atom, alinear or branched (C₁-C₈)alkyl group, a cycloalkyl group, a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, a (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylgroup, or the substituents of the pair (R_(c), R_(c)′), together withthe nitrogen atom carrying them, form a non-aromatic ring having from 5to 7 ring members, which ring may contain, in addition to the nitrogenatom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, whereinthe nitrogen in question may be substituted by a linear or branched(C₁-C₆)alkyl group, Cy₁, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independentlyof one another, represent a cycloalkyl group, a heterocycloalkyl group,an aryl group, or a heteroaryl group, n is an integer equal to 0 or 1,wherein: “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenylgroup, “heteroaryl” means any mono- or bi-cyclic group composed of from5 to 10 ring members, having at least one aromatic moiety and containingfrom 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic groupcontaining from 3 to 10 ring members, “heterocycloalkyl” means any mono-or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 9. The method according to claim 8, wherein R₁₀represents a hydrogen atom or a halogen atom.
 10. The method accordingto claim 1, wherein the compound of formula (I) is a compound of formula(I-e):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₂, R₃, R₄ and R₅ independently of one anotherrepresent a hydrogen atom, a halogen atom, a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a linear or branched(C₁-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(C₁-C₆)alkyl group, alinear or branched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyanogroup, a nitro group, -alkyl(C₀-C₆)—NR ₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′,—O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′,—NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′,—SO₂—NR₁₁R₁₁′, or —SO₂-alkyl(C₁-C₆), or the substituents of the pair(R₁, R₂), together with the carbon atoms carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by from 1 to 2groups selected from halogen, linear or branched (C₁-C₆)alkyl,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, R₆ and R₇independently of one another represent a hydrogen atom, a halogen atom,a linear or branched (C₁-C₆)alkyl group, a linear or branched(C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, alinear or branched (C₁-C₆)polyhaloalkyl, a hydroxy group, a linear orbranched (C₁-C₆)alkoxy group, a —S—(C₁-C₆)alkyl group, a cyano group, anitro group, -alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁,-alkenyl(C₂-C₆)-Cy₁, -alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), or the substituents of the pair (R₆, R₇), whengrafted onto two adjacent carbon atoms, together with the carbon atomscarrying them, form an aromatic or non-aromatic ring composed of from 5to 7 ring members, which ring may contain from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the resulting ringmay be substituted by a group selected from a linear or branched(C₁-C₆)alkyl group, —NR₁₃R₁₃′, -alkyl(C₀-C₆)-Cy₁ and oxo, W represents a—CH₂— group, a —NH— group or an oxygen atom, R₈ represents a hydrogenatom, a linear or branched (C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, anaryl group, a heteroaryl group, an arylalkyl(C₁-C₆) group, or aheteroarylalkyl(C₁-C₆) group, R₉ represents a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂,-alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃,-alkynyl(C₂-C₆)—O—Cy₂, -Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogenatom, a cyano group, —C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₁ and R₁₁′independently of one another represent a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group, or the substituents of the pair (R₁₁,R₁₁′), together with the nitrogen atom carrying them, form an aromaticor non-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, wherein the nitrogen may besubstituted by a hydrogen atom or a linear or branched (C₁-C₆)alkylgroup, R₁₂ represents -Cy₅, -Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆,-Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇, —C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁,—NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁₁, —SO₂—R₁₁, —C(O)—OR₁₁, or—NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′, independently of one another,represent a hydrogen atom, or an optionally substituted linear orbranched (C₁-C₆)alkyl group, R₁₄ represents a hydrogen atom, a hydroxygroup, or a hydroxy(C₁-C₆)alkyl group, R_(a) represents a hydrogen atomor a linear or branched (C₁-C₆)alkyl group, R_(b) represents a—O—C(O)—O—R_(c) group, a —O—C(O)—NR_(c)R_(c)′ group, or a—O—P(O)(OR_(c))₂ group, R_(c) and R_(c)′, independently of one another,represent a hydrogen atom, a linear or branched (C₁-C₈)alkyl group, acycloalkyl group, a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, a(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl group, or the substituents of the pair(R_(c), R_(c)′), together with the nitrogen atom carrying them, form anon-aromatic ring having from 5 to 7 ring members, which ring maycontain, in addition to the nitrogen atom, from 1 to 3 heteroatomsselected from oxygen and nitrogen, wherein the nitrogen in question maybe substituted by a linear or branched (C₁-C₆)alkyl group, Cy₁, Cy₂,Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independently of one another, represent acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group, n is an integer equal to 0 or 1, wherein: “aryl” meansa phenyl, naphthyl, biphenyl, indanyl or indenyl group, “heteroaryl”means any mono- or bi-cyclic group composed of from 5 to 10 ringmembers, having at least one aromatic moiety and containing from 1 to 3heteroatoms selected from oxygen, sulphur and nitrogen, “cycloalkyl”means any mono- or bi-cyclic non-aromatic carbocyclic group containingfrom 3 to 10 ring members, “heterocycloalkyl” means any mono- orbi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 11. The method according to claim 1, wherein atleast one of the groups selected from R₂, R₃, R₄ and R₅ does notrepresent a hydrogen atom.
 12. The method according to claim 1, whereinR₁₄ represents a hydrogen atom.
 13. The method according to claim 1,wherein R₁ represents a linear or branched (C₁-C₆)alkyl group or ahalogen atom.
 14. The method according to claim 1, wherein R₂ representsa linear or branched (C₁-C₆)alkoxy group, a hydroxy group or a halogenatom.
 15. The method according to claim 1, wherein R₃ represents ahydrogen atom, a hydroxy group, a linear or branched (C₁-C₆)alkoxy groupor —O-alkyl(C₁-C₆)—NR₁₁R₁₁′.
 16. The method according to claim 1,wherein R₄ and R₅ represent a hydrogen atom.
 17. The method according toclaim 1, wherein


18. The method according to claim 1, wherein the substituents of thepair (R₁, R₅) are identical and the substituents of the pair (R₂, R₄)are identical.
 19. The method according to claim 1, wherein R₆represents a hydrogen atom, an optionally substituted linear or branched(C₁-C₆)alkoxy group or a —O-alkyl(C₁-C₆)—R₁₂ group.
 20. The methodaccording to claim 1, wherein R₇ represents a hydrogen atom.
 21. Themethod according to claim 1, wherein


22. The method according to claim 1, wherein the compound of formula (I)is a compound of formula (I-g):

wherein the ring system

is selected from the group consisting of:

R₁ represents a halogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl group, ahydroxy group, a hydroxy(C₁-C₆)alkyl group, a linear or branched(C₁-C₆)alkoxy group, —S—(C₁-C₆)alkyl, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—NR₁₁R₁₁′, —O-alkyl(C₁-C₆)—R₁₂,—C(O)—OR₁₁, —O—C(O)—R₁₁, —C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′,—NR₁₁—C(O)—OR₁₁′, -alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′,—SO₂-alkyl(C₁-C₆), R₆ and R₇ independently of one another represent ahydrogen atom, a halogen atom, a linear or branched (C₁-C₆)alkyl group,a linear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a linear or branched (C₁-C₆)polyhaloalkyl, ahydroxy group, a linear or branched (C₁-C₆)alkoxy group, a—S—(C₁-C₆)alkyl group, a cyano group, a nitro group,-alkyl(C₀-C₆)—NR₁₁R₁₁′, —O—Cy₁, -alkyl(C₀-C₆)-Cy₁, -alkenyl(C₂-C₆)-Cy₁,-alkynyl(C₂-C₆)-Cy₁, —O-alkyl(C₁-C₆)—R₁₂, —C(O)—OR₁₁, —O—C(O)—R₁₁,—C(O)—NR₁₁R₁₁′, —NR₁₁—C(O)—R₁₁′, —NR₁₁—C(O)—OR₁₁′,-alkyl(C₁-C₆)—NR₁₁—C(O)—R₁₁′, —SO₂—NR₁₁R₁₁′, —SO₂-alkyl(C₁-C₆), or thesubstituents of the pair (R₆, R₇), when grafted onto two adjacent carbonatoms, together with the carbon atoms carrying them, form an aromatic ornon-aromatic ring composed of from 5 to 7 ring members, which ring maycontain from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the resulting ring may be substituted by a groupselected from a linear or branched (C₁-C₆)alkyl group, —NR₁₃R₁₃′,-alkyl(C₀-C₆)-Cy₁ and oxo, W represents a —CH₂— group, a —NH— group oran oxygen atom, R₈ represents a hydrogen atom, a linear or branched(C₁-C₈)alkyl group, a —CHR_(a)R_(b) group, an aryl group, a heteroarylgroup, an arylalkyl(C₁-C₆) group, or a heteroarylalkyl(C₁-C₆) group, R₉represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, -Cy₂, -alkyl(C₁-C₆)-Cy₂, -alkenyl(C₂-C₆)-Cy₂,-alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃, -alkynyl(C₂-C₆)—O—Cy₂,-Cy₂-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₃, a halogen atom, a cyano group,—C(O)—R₁₅, or —C(O)—NR₁₅R₁₅′, R₁₁ and R₁₁′ independently of one anotherrepresent a hydrogen atom, a linear or branched (C₁-C₆)alkyl group, orthe substituents of the pair (R₁₁, R₁₁′), together with the nitrogenatom carrying them, form an aromatic or non-aromatic ring having from 5to 7 ring members, which ring may contain, in addition to the nitrogenatom, from 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen, wherein the nitrogen may be substituted by a hydrogen atom ora linear or branched (C₁-C₆)alkyl group, R₁₂ represents -Cy₅,-Cy₅-alkyl(C₀-C₆)—O-alkyl(C₀-C₆)-Cy₆, -Cy₅-alkyl(C₀-C₆)-Cy₆,-Cy₅-alkyl(C₀-C₆)—NR₁₁-alkyl(C₀-C₆)-Cy₆, -Cy₅-Cy₆-O-alkyl(C₀-C₆)-Cy₇,—C(O)—NR₁₁R₁₁′, —NR₁₁R₁₁′, —OR₁₁, —NR₁₁—C(O)—R₁₁′, —O-alkyl(C₁-C₆)—OR₁₁,—SO₂—R₁₁, —C(O)—OR₁₁, or —NH—C(O)—NH—R₁₁, R₁₃, R₁₃′, R₁₅ and R₁₅′,independently of one another, represent a hydrogen atom, or anoptionally substituted linear or branched (C₁-C₆)alkyl group, R₁₄represents a hydrogen atom, a hydroxy group, or a hydroxy(C₁-C₆)alkylgroup, R_(a) represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, R_(b) represents a —O—C(O)—O—R_(c) group, a—O—C(O)—NR_(c)R_(c)′ group, or a —O—P(O)(OR_(c))₂ group, R_(c) andR_(c)′, independently of one another, represent a hydrogen atom, alinear or branched (C₁-C₈)alkyl group, a cycloalkyl group, a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, a (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylgroup, or the substituents of the pair (R_(c), R_(c)′), together withthe nitrogen atom carrying them, form a non-aromatic ring having from 5to 7 ring members, which ring may contain, in addition to the nitrogenatom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, whereinthe nitrogen in question may be substituted by a linear or branched(C₁-C₆)alkyl group, Cy₁, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇, independentlyof one another, represent a cycloalkyl group, a heterocycloalkyl group,an aryl group, or a heteroaryl group, n is an integer equal to 0 or 1,wherein: “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenylgroup, “heteroaryl” means any mono- or bi-cyclic group composed of from5 to 10 ring members, having at least one aromatic moiety and containingfrom 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic groupcontaining from 3 to 10 ring members, “heterocycloalkyl” means any mono-or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ringmembers, and containing from 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen, which may include fused, bridged or spiro ringsystems, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may besubstituted by from 1 to 4 groups selected from optionally substitutedlinear or branched (C₁-C₆)alkyl, optionally substituted linear orbranched (C₂-C₆)alkenyl, optionally substituted linear or branched(C₂-C₆)alkynyl, optionally substituted linear or branched (C₁-C₆)alkoxy,optionally substituted (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —C(O)—OR′, —O—C(O)—R′, —C(O)—NR′R″,—O—C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, —O—P(O)(OR′)₂, —O—P(O)(O⁻M⁺)₂,linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy, halogen, oran aldohexose of formula:

in which each R′ is independent; wherein R′ and R″, independently of oneanother, represent a hydrogen atom or an optionally substituted linearor branched (C₁-C₆)alkyl group, and M⁺ represents a pharmaceuticallyacceptable monovalent cation, its enantiomers, diastereoisomers andatropisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 23. The method according to claim 1, wherein R₈represents a hydrogen atom, a —CHR_(a)R_(b) group, an optionallysubstituted linear or branched (C₁-C₈)alkyl group, or aheteroarylalkyl(C₁-C₆) group.
 24. The method according to claim 1,wherein R₉ represents a hydrogen atom, a halogen atom, a linear orbranched (C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group,a linear or branched (C₂-C₆)alkynyl group, an aryl group or a heteroarylgroup.
 25. The method according to claim 1, wherein R₁₁ and R₁₁′,independently of one another, represent a linear or branched(C₁-C₆)alkyl group, or the substituents of the pair (R₁₁, R₁₁′),together with the nitrogen atom carrying them, form a non-aromatic ringhaving from 5 to 7 ring members, which ring may contain, in addition tothe nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulphurand nitrogen, wherein the nitrogen may be substituted by a hydrogen atomor a linear or branched (C₁-C₆)alkyl group.
 26. The method according toclaim 1, wherein R₁₂ represents -Cy₅ or -Cy₅-alkyl(C₀-C₆)-Cy₆.
 27. Themethod according to claim 26, wherein Cy₅ represents a heteroaryl group.28. The method according to claim 26, wherein Cy₆ represents a phenylgroup.
 29. The method according to claim 26, wherein R₁₂ represents

wherein p is an integer equal to 0 or 1 and R₁₆ represents a hydrogenatom, a hydroxy group, an optionally substituted linear or branched(C₁-C₆)alkyl group, a linear or branched (C₁-C₆)alkoxy group, a—O—(CHR₁₇—CHR₁₈—O)_(q)—R′ group, a —O—P(O)(OR′)₂ group, a —O—P(O)(O⁻M⁺)₂group, a —O—C(O)—NR₁₉R₂₀ group, a di(C₁-C₆)alkylamino(C₁-C₆)alkoxygroup, a halogen atom, or an aldohexose of formula:

in which each R′ is independent; wherein: R′ represents a hydrogen atomor a linear or branched (C₁-C₆)alkyl group, R₁₇ represents a hydrogenatom or a (C₁-C₆)alkoxy(C₁-C₆)alkyl group, R₁₈ represents a hydrogenatom or a hydroxy(C₁-C₆)alkyl group, R₁₉ represents a hydrogen atom or a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, R₂₀ represents a(C₁-C₆)alkoxy(C₁-C₆)alkyl group, a —(CH₂)_(r)—NR₁₁R₁₁′ group or a—(CH₂)_(r)—O—(CHR₁₇—CHR₁₈—O)_(q)—R′ group, q is an integer equal to 1, 2or 3 and r is an integer equal to 0 or 1, M⁺ represents apharmaceutically acceptable monovalent cation.
 30. The method accordingto claim 29, wherein the aldexose is D-mannose.
 31. The method accordingto claim 1, wherein the compound of formula (I) is selected from thegroup consisting of:(2R)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;(2R)-2-{[5-{3-chloro-2-ethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;N-[(5S_(a))-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine;(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzothiophen-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicacid;(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoicacid;(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-fluoro-2-(4-fluorophenyl)-1-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoicacid;(2R)-2-{[3-{(3S_(a))-3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)-1-methyl-1H-indol-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;(2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid;1-[(dimethylcarbamoyl)oxy]ethyl(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;1-[(ethoxycarbonyl)oxy] ethyl(2R)-2-{[(3S_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-b]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine;N-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenylalanine;and2-{[(3R_(a))-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.
 32. The method accordingto claim 1, wherein the condition is selected from cancer, auto-immunediseases, and immune system diseases.
 33. The method according to claim32, wherein the condition is selected from cancers of the bladder,brain, breast and uterus, chronic lymphoid leukaemias, cancer of thecolon, oesophagus and liver, lymphoblastic leukaemias, acute myeloidleukaemias, lymphomas, melanomas, malignant haemopathies, myelomas,ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreaticcancer and small-cell lung cancer.
 34. The method according to claim 1,wherein the condition is cancer, and the compound of formula (I) isadministered in combination with an anti-cancer agent selected fromgenotoxic agents, mitotic poisons, anti-metabolites, proteasomeinhibitors, kinase inhibitors and antibodies, wherein the compound offormula (I) and the anti-cancer agent may be administered in combinationwith one or more pharmaceutically acceptable excipients.
 35. The methodof claim 1, wherein the condition is cancer requiring radiotherapy.